Investigating interleukin-8 in Alzheimer's disease: A comprehensive review

Abstract

Several studies indicate that the development of Alzheimer's disease (AD) has strong interactions with immune mechanisms within the brain, indicating a close association between inflammation in the central nervous system and the progression of neurodegeneration. Despite considerable progress in understanding the inflammatory aspects of AD, several of them remain unresolved. Pro-inflammatory cytokines and microglia are pivotal components in the inflammatory cascade. Among these, the role of interleukin-8 (IL-8) in neurodegeneration seems complex and multifaceted, involving inflammation, neurotoxicity, blood-brain barrier disruption, and oxidative stress, and is still poorly characterized. We conducted a review to describe the evidence of IL-8 involvement in AD. IL-8 is a cytokine known for its proinflammatory properties and typically produced by macrophages, predominantly functions as a chemotactic signal for attracting neutrophils to inflamed sites in the bloodstream. Interestingly, IL-8 is also present in the brain, where it is primarily released by microglia in response to inflammatory signals. This review aims to provide a comprehensive overview of the structure, function, and regulatory mechanisms of IL-8 relevant to AD pathology.

Keywords

Alzheimer's disease amyloid-β dementia immunity interleukin-8 neurodegeneration neuroinflammation

Introduction

Alzheimer's disease (AD) represents the most common form of dementia worldwide, and it is unanimously considered a prototypic form of neurodegenerative disease.¹ However, once AD is diagnosed, neuronal loss and neuropathologic lesions have already occurred in several brain regions,² making it challenging to study the early stages of the disease and the various pathogenic pathways involved in the development of this neurodegenerative process. The clinical manifestations of the disease usually begin with mild memory difficulties and progress to full cognitive impairment, with other cognitive domains getting impaired, including language, judgment and behavior.³ From a pathological perspective, AD brains are specifically characterized by the accumulation of amyloid-β (Aβ) extracellular plaques and the formation of intracellular neurofibrillary tangles.⁴ The Aβ accumulation is a complex and still not fully characterized process in its finer details, wherein essentially there is an excess production of protein more or less associated with a deficit in its clearance. Recent studies highlighter the role of the insufficient capability of microglial activity in this process.⁵ In addition to these essential features, several other pathways contribute to AD pathogenesis, including altered protein degradation, neuroinflammation, blood-brain barrier (BBB) disruption, oxidative stress, and diminished support from neurotrophic factors.⁶ In recent years emerging evidence highlighted the role of inflammation in AD, as demonstrated by activated microglia within and around senile plaques,⁷ which induces the release of various pro-inflammatory cytokines.⁸

Positron emission tomography (PET) radioligands, particularly those targeting activated microglial proteins like translocator protein 18 kDa (TSPO), now enable for assessing neuroinflammation in vivo.^9,10 TSPO PET has offered crucial insights into the temporal and spatial relationship between neuroinflammation and AD pathology, with some studies suggesting that neuroinflammation may interact with amyloid plaques to drive intracellular tau tangles spreading across Braak stages.^10,11 Despite ongoing advances in PET tracer development,^10,11 studying the complexity of microglial activation and the underlying molecular mechanisms—such as the production of pro-inflammatory cytokines—remains challenging with this imaging technique. In this context, fluid biomarkers may offer a more suitable approach to delve into these molecular dynamics.

Recently, the levels of several inflammatory cytokines/chemokines such as Interleukin-8 (IL-8), IL-6, IL-1, tumor necrosis factor-alpha (TNF-α), and monocyte chemotactic protein 1 (MCP-1 or CCL2) were found to be elevated in patients with AD.^12,13 IL-8, alternatively referred to as chemokine C-X-C motif ligand 8 (CXCL8), is a proinflammatory cytokine generated by microglia. Its primary role lies in serving as a chemotactic cue, primarily directing neutrophils toward sites of inflammation within the bloodstream.¹⁴ In addition to human neutrophils, IL-8 activates T cells, B cells, basophils, IL-2-activated natural killer cells and granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-3-stimulated eosinophils.¹⁵ Increased peripheral IL-8 production has been reported in patients with various inflammatory and autoimmune diseases, infections, and cancers.^14,16 IL-8 has been demonstrated to be predominantly produced and released by microglia and astrocytes in the brain.^17,18 IL-8 is synthesized at the onset of inflammatory response, potentially enduring for days or weeks, in contrast to other inflammatory cytokines which typically are produced and dispersed within a few hours.¹⁹ There is evidence of IL-8 increased levels in cerebrospinal fluid (CSF) of patients with AD as well as a positive correlation between CSF IL-8 levels with age.²⁰ IL-8 is associated with a wide array of biological effects that may be relevant for AD pathogenesis, including the activation of chemotaxis for inflammatory cells, the generation of reactive oxygen species, the upregulation of the expression of integrin CD11b–CD18, the facilitation of cell adhesion to endothelial cells, the promotion of angiogenesis, and finally the curbing of histamine release.²¹ While the detailed characterization of the involvement of IL-8 in the progression of AD still largely remains unclear, this review aims to summarize and consolidate the current evidence supporting the IL-8 role in its pathogenesis.

Methods

For this systematic review, the authors undertook a comprehensive search for relevant literature. They initially explored databases such as PubMed, Embase, and Google Scholar, as well as their personal article collections. Their search utilized specific terms including “Interleukin −8 AND Alzheimer's disease,” “CXCL8 AND Alzheimer's disease,” and “neuroinflammation AND Alzheimer's Disease.” Articles not meeting certain criteria, such as being in a language other than English, published before the 1990s, or existing solely as abstracts, were excluded unless they were deemed pertinent. The authors then evaluated the abstracts of the selected articles, focusing on those aligned with the review's objectives. Subsequently, a thorough examination of the chosen articles was conducted, with emphasis on factors like participant cohort size, clinical relevance, methodological rigor, and avoidance of redundancy. Initially, 612 articles were identified, and after careful assessment, 134 articles were included in the review. Among these, 17 primarily centered on in vitro studies, while 21 studies predominantly involved human study cohorts.

Alzheimer's disease pathology and immunity

The role of inflammation in the pathogenesis and progression of AD has been extensively investigated, and a comprehensive discussion of the topic is beyond the scope of our review and can be found elsewhere.^22–26 The role of innate immunity,²⁷ adaptive immunity,^22,28 and numerous molecules such as cytokines and chemokines have been explored as possible mechanisms influencing the onset and the evolution of AD.^29–31 Pro-inflammatory cytokine signalling plays various roles in both neurodegeneration and neuroprotection. Multiple pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), p38 mitogen-activated protein kinases (p38 MAPKs), protein kinase B (Akt)/ mammalian target of rapamycin (mTOR), caspases, nitric oxide, and cyclooxygenase (COX) activate microglia and astrocytes stimulating the production of inflammatory cytokines like TNF-α, interleukins, and chemokines, potentiating the neuroinflammatory process in the brain contributing to the pathology of AD.³¹ Figure 1 depicts the activation of Inflammation in AD.

Figure 1.

Schematic activation of Inflammation in AD. This illustration has attempted to point out the role of microglia and astrocytes in the inflammatory response in relation to AD. Microglia and astrocytes are shown as key cellular players that release chemokines and other inflammatory mediators in response to pathological stimuli, such as amyloid-β and tau aggregates. Such signalling molecules participate in the activation of a chronic inflammatory state that promotes neuronal damage and thereby accelerates the neurodegenerative process of AD.

Inflammageing and Alzheimer's disease

Ageing significantly influences the pathogenesis of AD; it also impacts the body's innate immunity.³² Human ageing is characterized by chronic, low-level inflammation, and functional modifications of the immune response, often referred to as “inflammageing”.³³ Inflammageing contributes to several age-related diseases, including AD.^34–36

Age-induced biochemical alterations promote transcriptional activation of NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasomes, which are intracellular multicomponent structures that enable the secretion of IL-1β and IL-18, and this activation exacerbates many aspects of neurodegeneration.³⁷ Concerning AD, the NLRP3 inflammasome has emerged as a critical molecular player in the pathogenesis of the disease. In response to stimuli such as Aβ oligomers and tau aggregates, microglia and astrocytes trigger chronic neuroinflammatory responses, neuronal death, and pyroptosis via intracellular NLRP3 inflammasome activation.^38,39 Interestingly, pharmacological inhibition of NLRP3 inflammasome has shown promising neuroprotective effects, reducing Aβ deposition and ameliorating cognitive impairment in AD animal models.⁴⁰ Furthermore, the activation of NLRP3 inflammasome has been implicated in the deposition and spread of Aβ, somehow confirming that NLRP3 inflammasome activation and the typical modifications of AD pathology are linked.^41,42 In fact, recent studies have highlighted the involvement of NLRP3 inflammasome in tau pathology, further underscoring the role of immune activation in the pathogenesis of the disease.^43,44

Another important aspect of immune response in AD is related to the activation of the innate immune system and glial cells. This process is thought to occur in the early stages of the disease and also to contribute to its progression.⁴⁵ Mild activation of microglia facilitates the clearance of cellular debris, and damaged neurons in the brain. However, a persistent increased activation of microglia and astrocytes may become toxic to neuronal cells.⁴⁶

Prolonged chronic inflammation sustains elevated levels of cytokines and chemokines severely impacting neuronal survival.⁴⁷ Furthermore, Aβ itself can trigger the expression of several pro-inflammatory cytokines, such as TNF-α, IL-6, interferon-γ (IFN-γ) and IL-1β by glial cells, and several chemokines, including MCP-1, IL-8, CXCL10 (IP-10), and CCL5, increasing the recruitment of immune cells from the peripheral blood.⁴⁶ Those immune cells with receptors can cross the BBB contributing to the inflammatory response in the brain.⁴⁸ In healthy ageing, BBB undergoes numerous alterations, which could be considered adaptive or reactive responses to age-related conditions. Ageing makes the BBB in AD more vulnerable to inflammatory cytokines. Consequently, BBB damage tends to attract additional peripheral immune cells and cytokines into the brain parenchyma, thereby triggering neuroinflammation.⁴⁸ Understanding the interplay between low-grade systemic inflammation, neuroinflammation, and neurodegeneration is essential for advancing diagnostic and therapeutic approaches.

Insights from PET studies

Research on PET tracers, particularly those targeting TSPO and newer ligands with enhanced imaging quality and reduced nonspecific binding, has shown that microglial activation can be detected early in AD.^9,10 The hypothetical model of dynamic biomarkers in AD proposed by Calsolaro and Edison (2016),⁴⁹ which incorporates PET studies evaluating neuroinflammation, suggests that microglial activation may begin in the very earliest phases of cognitive impairment, especially in the context of systemic inflammation and triggered by early amyloid peptides and fibrils. This activation is thought to stabilize at a plateau and then increase again in the later stages of AD when amyloid plaques are formed. While early microglial activation aids in clearing debris and damaged neurons, sustained activation is associated with worsening glucose metabolism, impaired synaptic function, and increased neurodegeneration.

Key concepts:

- Inflammation plays a dual role in AD, contributing both to neurodegeneration and neuroprotection. Key pathways like NF-κB and mTOR activate microglia and astrocytes, leading to the production of inflammatory cytokines and chemokines that contribute to AD pathology.

-Ageing-related chronic inflammation, known as “inflammageing,” significantly influences AD pathogenesis. The NLRP3 inflammasome, activated by stimuli like Aβ oligomers and tau aggregates, is a crucial molecular player in AD, driving neuroinflammation, neuronal death, and pyroptosis.

Interleukin-8

Molecular structure of IL-8 and regulation of IL-8 expression

IL-8 is a member of the CXC chemokine family, which are small molecular weight proteins (8–12 kDa) characterized by the presence of two conserved cysteine CXC residue motif (C-cysteine, X-any other residue), proximal to the N-terminal region separated by a single amino acid.^50,51 In the CXC-chemokines family, the IL-8 subgroup has an amino acid sequence Glu-Leu-Arg (ELR) preceding the first conserved cysteine residue in the primary structure of these proteins.⁵¹ Murine CXCL-1 is commonly regarded as the functional equivalent of human IL-8.⁵² Both CXCL-1 and IL-8 exhibit chemoattractant properties towards neutrophils and are implicated in angiogenesis.⁵³ Interestingly, the capacity of IL-8 to induce angiogenesis is distinct from its ability to initiate inflammation.⁵⁴

IL-8, the product of this gene, is a small soluble peptide weighing between 8 to 10 kDa. Initially, a precursor protein containing 99 amino acids is synthesized, and subsequently, through distinct cleavage processes, various active IL-8 subtypes are generated, with lengths ranging from 69 to 79 amino acids, including 79, 77, 72, 71, and 69 amino acids.⁵⁵ Peptides of 72 and 77 amino acids are the most biologically relevant. The 72 amino acid peptide is the major form secreted by monocytes and macrophages, whereas the 77 amino acid variant is the most abundant secretory product of nonimmune cells. The monomeric peptide configuration of IL-8 comprises an NH₂-terminal loop, three antiparallel beta-strands linked by loops, and a C-terminal alpha helix.⁵⁶ Typically, CXC chemokines can dimerize. Dimerization in IL-8 takes place through the interaction of side chains located in its initial β-strand, which is then stabilized by its C-terminal α-helix and two disulfide bridges (Cys7-Cys34 and Cys9-Cys50). IL-8 exists in both monomeric and dimeric states. Monomers and dimers have different concentrations across diverse locations and temporal periods. Mutations or truncations affecting the structural integrity in specific regions may lead to the production of IL-8 mutants incapable of dimerization.⁵⁷ These alterations could involve the removal of C-terminal residues crucial for α-helix formation or changes to residues within one of the β-strands.⁵⁸ The monomeric form of IL-8 is the biologically active form which has the dimerization ability to maintain full inflammatory activity in vivo.⁵⁹ IL-8 expression is low in normal tissues,⁶⁰ but can be stimulated significantly, sometimes increasing by up to 100 times, by factors such as IL-1, TNF-α, IL-6, IFN-α, lipopolysaccharide, reactive oxygen species, and various other cellular stresses.^60,61 Conversely, dexamethasone, IL-4, and IL-10 represent important inhibitors of IL-8 production.⁶² The transcriptional regulation of IL-8 synthesis integrates signals from various intracellular signalling pathways and seems to vary depending on whether the trigger for upregulation is cytokine or cellular stress. The regulation of IL-8 gene expression relies significantly on its 5’ flanking region. Il-8 gene has a promoter with binding sites for several factors, including NF-κB, which represents one of the main ones.⁶³ In parallel, the 3’ untranslated region of the gene contains an AU-rich RNA instability element (ARE) regulated by MEKK1, MKK6, and p38 MAP kinase which are critical for determining the half-life of IL-8 mRNA.⁶⁴

Physiological function and receptors of IL-8 expression

As discussed, IL-8 plays an important role in the recruitment of neutrophils and other immune cells to inflammatory regions and is implicated in various inflammatory-mediated diseases such as inflammatory bowel diseases, rheumatoid arthritis, psoriasis, asthma, cystic fibrosis, and AD.⁶⁵ IL-8 is generally viewed as a pro-inflammatory cytokine responsive to oxidative stress, prompting the secretion of lysosomal enzymes, increased expression of adhesion molecules, and raised levels of intracellular calcium.^66–68 IL-8 also plays a pivotal role in the brain, especially by recruiting activated microglia. Interestingly, its levels have been found elevated in the serum, CSF, and brains of individuals affected by AD compared to controls.⁶⁹ IL-8 can play a key role in normal tissues and tumors by activating PI3K-Akt, PLC, JAK-STAT, and other signalling pathways after combining with CXCR1/2. IL-8 interacts with two G protein-coupled receptors (GPCRs), namely CXCR1 and CXCR2, which are both located on chromosome 2q35 and share a similar aminoacidic sequence Interleukin-8 promotes cell migration via CXCR1 and CXCR2 in liver cancer Interleukin-8 promotes cell migration via CXCR1 and CXCR2 in liver cancer.⁷⁰ These two transmembrane receptors have seven transmembrane domains in the middle, including 3 extracellular loops and 3 intracellular loops. Their N-terminal is located outside the cell and the C-terminal is located inside the cell.⁷¹ CXCR1 exclusively demonstrates high affinity binding with IL-8, while CXCR2 binds seven distinct chemokines (CXCL1-3, 5–8) with comparable high affinity to facilitate neutrophil responses.⁷² IL-8, both as monomers and dimers, exhibit distinct activities and regulation on CXCR1 and CXCR2 receptors.⁷³ Neutrophil recruitment and activation entail continuous interaction with both receptors, encompassing functions such as chemotaxis and cytotoxic events. During the initial stages of recruitment, CXCR2 exhibits a more significant role, while following CXCR2 depletion via exocytosis, CXCR1 may assume a greater significance. At the infection site, CXCR1 is the main receptor on the cell surface, and its activation leads to cytotoxic events such as the release of proteases and superoxide. Both CXCR1 and CXCR2 are expressed in different tissues, in the brain they are present in neurons, astrocytes, and microglia but their function in the CNS remains poorly understood.⁵⁸ CXCR2 is involved in angiogenesis, and it is expressed in endothelial cells which causes proliferation, tube formation, and migration of epithelial cells, leading to the formation of new blood vessels.⁷⁴

Impact of IL-8 on the recruitment of activated microglia

Endothelial cells form a physical part of the BBB and contribute to homeostasis within the CNS, preventing potentially detrimental leukocyte interactions by maintaining tight and adherens junctions. The inflammatory mediators increase the vascular permeability, in that they can cause profound changes between cell-cell adherence of endothelial cells mediated by tight and adherens junctions via a Rho/Rho-kinase pathway. Activated endothelial cells express adhesion molecules and selectins mediating leukocyte; rolling, polarization to the site of inflammation and arrest on the segment between Selectin-expressing sites. Expression of TNFR1, TNFR2, CXCR1, CXCR3R CCB can regulate the barrier acting as permeability factors and facilitate inflammation by releasing chemokines like IL-8 or pro-inflammatory cytokines such as TNF-α.^75,76 Brain endothelial cells can produce CCL2 and CXCL8. Their expression increases after TNF-α stimulation or infection.⁷⁷ In addition, IL-8 activates peripheral endothelial cells leading to upregulation of adhesion molecules, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion protein 1 (VCAM-2), which facilitate the transmigration to the CNS. Cross-linking between the two adhesion proteins stimulates endothelial cells to produce more IL-8 and RANTES by upregulating mRNA expression, protein secretion, and activation of MAP kinases—ERK1 + . Upregulation of chemokine production by MAP kinase-mediated stimulus to ICAM-1 would have a pro-inflammatory effect since it could lead to both leukocyte attraction and activation.⁷⁸

Anti-IL-8 monoclonal antibodies decrease the activation of endothelial cells, reducing the expression of adhesion molecules and subsequent immune cell infiltration into the CNS.⁷⁹

SASP (senescence-associated secretory phenotype) secretory factors promote the accumulation of senescent glial cells, including astrocytes and microglia, particularly the accumulation of high levels of p16INK4A protein in these cells leads to cell cycle arrest, neuronal loss, and cognitive decline. Senescent cell targeting may reduce inflammation and mitigate disease progression. A study by Bussian et al. (2018) provides direct evidence linking senescent cells to AD progression. Selective elimination of senescent astrocytes and microglia in a mouse model of AD demonstrated reduced neuroinflammation and improved cognitive function. Senescent cells in the brain were characterized by high expression of p16INK4A, a key indicator of cellular senescence, such senescent cells secrete various inflammatory factors, which include a variety of proinflammatory cytokines, chemokines, including IL-8, which contribute to the neuroinflammatory environment associated with AD senescent glial cells prevents tau-dependent pathology and cognitive decline.⁸⁰

Role for peripherally produced IL-8 in the pathogenesis of AD

The role that peripherally produced IL-8 may have in the pathogenesis of AD is still a matter of debate. Serum IL-8 concentrations were measured with a Luminex assay in a 2017 study by Zhu and colleagues⁸¹ in which the authors recruited subjects from three cohorts, the first including subjects without cognitive impairment, the second of subjects who were classified as “cognitive impairment no dementia” and finally the last cohort of subjects affected by AD. These authors found that high serum IL-8 levels were associated with the presence of AD and “cognitive impairment no dementia” only in the presence of imaging markers of cerebrovascular disease (in patients for whom MRI images were available). In particular, they were higher in patients with significant WMH, independently of factors such as age, gender, education, APOE ε4 carrier status, diabetes mellitus, hypertension, cardiovascular diseases, as well as cortical infarct and lacunes. A previous study by Narasimhalu and colleagues, in 2015, conducted on 243 ischemic stroke patients, also found that higher serum IL-8 concentration is independently associated with baseline cognitive impairment following ischemic stroke.⁸² Similarly, in the study by Corsi and collaborators in 2011, serum IL-8 levels measured with Biochip Array Technology were found to be high in AD patients⁸³ as well as in the 2012 study by Alsadany and colleagues, in which serum IL-8 concentrations were measured by enzyme-linked immunosorbent assay (ELISA).⁶⁹ In contrast, Kim and colleagues obtained completely opposite results, documenting lower serum IL-8 levels in subjects with AD and mild cognitive impairment (MCI) compared to healthy controls.⁸⁴

IL-8 polymorphism and AD risk

The Il8 gene is situated on chromosome 4q13.3 and comprises four exons and three introns, genetic variants in this gene may affect AD risk. Case reports show that Chromosome 4q13.3 deletions have been reported to be related to intellectual disability, delayed speech and language development. The deletion includes three genes ADAMTS3, ANKRD17, and COX18. ADAMTS3 encodes a metalloprotease critical for procollagen processing, expressed in cartilage and bones, with mutations causing craniofacial and skeletal anomalies. ANKRD17 encodes a protein vital for vascular integrity and DNA replication, with deletions leading to heart defects and inhibited cell cycle progression. COX18 has no clear role, pseudogenes associated with it may regulate genes, with RNU4ATAC mutations causing cognitive delays in Roifman syndrome.^85,86

A recent study has suggested the association between IL-8 gene −251T > A polymorphism and increased susceptibility to AD.⁸⁷ Based on the ethnicity a significantly increased risk of AD associated with IL-8 gene −251T > A variant has been revealed among Asians in all 5 genetic models and Europeans in three genetic models, however further validation of this association is necessary across additional populations.⁸⁸ This functional polymorphism, −251T > A, located in the proximal promoter region of the IL-8 gene, has consistently been linked to various inflammatory conditions including bronchial asthma,⁸⁹ gastritis,⁹⁰ and pancreatitis.⁹¹

A UK study found novel the IL8–251A allele. Results show how the −251A allele in the IL8 promoter region is associated with increased transcriptional activity and elevated IL-8 levels, which supports the idea that this polymorphism can influence IL-8 production. By measuring the IL-8 response to LPS stimulation in whole blood from 50 healthy donors, this study demonstrates that individuals with the −251A allele have an increased IL-8 production, suggesting that the polymorphism affects the transcriptional regulation of the IL-8 gene and thus the inflammatory response.^92,93

In a recent study, Li and colleagues focused on IL-8 −251 T/A polymorphism which influences the production of IL-8, and the methylenetetrahydrofolate reductase (MTHFR) gene 677 C/T variant, which affects homocysteine levels. Interestingly, the study found a critical role for IL-8/MTHFR interactions in the development of AD.⁹⁴

Figure 2 represents molecular structure, molecular pathway and the role of IL-8 during inflammatory response. Figure 3 depicts the interaction of IL-8 and its receptors expressed on CNS cells.

Figure 2.

In this figure an overview of the key aspects of IL-8 is illustrated. A schematic diagram depicting the molecular structure, pathway, and role of IL-8 in inflammation is presented. The molecular structure of IL-8 has cysteine motifs, an ELR sequence, and dimerization sites that are important for its activity and interaction with receptors. IL-8 is involved in a few important molecular pathways, which include NF-κB and PI3 K/Akt, responsible for the regulation of its expression and functionality. Functionally, IL-8 acts as a potent neutrophil chemoattractant in the recruitment of such cells to sites of inflammation.

Figure 3.

Schematic representation of IL-8 and its receptors. Schematic representation of IL-8 and its receptors. Schematic representation of the IL-8/CXCR1 and IL-8/CXCR2 interaction highly expressed in the brain by neurons, astrocytes, and microglia. IL-8 binds these receptors on the surface of the CNS cells, highlighting their significance in neuroinflammatory processes.

Key concepts:

-Molecular Structure and Regulation: IL-8 is an ELR chemokine in the CXC family that can exist either as a monomer or a dimer as a biologically active form.

- Physiological Function and Receptors: IL-8 is involved in the recruitment of neutrophils to sites of inflammation and other immune cells by exerting its effects via the CXCR1 and CXCR2 receptors. Thus, the interactions of IL-8 in such as processes as chemotaxis, angiogenesis, and neuroinflammation implicate it in AD.

- IL-8 Gene Polymorphism and Risk of AD: The IL8 gene is regarded as a functional polymorphism (−251T > A) on chromosome 4q13.3 and is associated with increased production of IL-8, predisposing to several inflammatory diseases. A possible association between this polymorphism and an increased risk of AD has thus been suggested in certain ethnic populations.

Research studies

In vitro investigations elucidating the role of IL-8 in AD pathogenesis

This paragraph examines the findings of in vitro studies exploring the involvement of IL-8 in various aspects of AD progression and pathology. The main findings are summarized in Table 1.

Table 1.

Main evidence from in vitro studies.

Reference	Methods	Cell type cultures	Main Findings
Aloisi et al.⁹⁵	ELISA, bioassay, RT-PCR, western blotting	Astrocyte-derived from human embryonic brain Cell culture	Astrocytes and microglia, produce IL-8 when stimulated by inflammatory signals like TNF-α and IL-1β.
Ehrlich et al.¹⁸	ELISA, RT-PCR, quantitative analysis	Human fetal microglia cell culture	Human fetal microglia produce IL-8 when stimulated by LPS, IL-1β, and TNF-α, while pretreatment with IL-4, IL-10, or TGF-β inhibited this production.
Ashutosh et al.⁹⁶	ELISA, cell viability assays, apoptosis assays, RT-PCR	Human fetal astrocytes, microglia, and neurons	Ashutosh and colleagues found IL-8 may provide neuroprotection by enhancing BDNF production and suppressing Aβ-induced neuronal apoptosis in vitro.
Franciosi et al.¹⁰⁰	RT-PCR, ELISA, and immunocytochemistry techniques	Human fetal microglia cell culture	IL-8 effects on Aβ₁₋₄₂ increased pro-inflammatory cytokine expression and production, IL-8 alone had minimal effects but significantly enhanced cytokine expression when combined with Aβ₁₋₄₂, suggesting IL-8 exacerbates Aβ₁₋₄₂-induced inflammation in microglia.
Walker et al.¹⁰¹	RT-PCR, gene array profiling in	Human postmortem brain microglia	Gene array profiling of Aβ₁₋₄₂ stimulated showed upregulation of IL-8 showing an 11.7-fold increase in RNA expression.
Lue et al.¹⁰²	Reactive nitrogen intermediate assay, ELISA, quantitative analysis	Microglia and astrocyte cultures	Increase in pro-inflammatory cytokine production: pro-IL-1β, IL-6, TNF-α, MCP-1, MIP-1α, IL-8, and M-CSF in cell cultured from postmortem brain autopsies of AD patients upon exposure to pre-aggregated Aβ_1–42.
Griciuc et al.¹⁰³	5xFAD mice, behavioral tests, culture FACS, ELISA, immunohistochemistry and RNA-seq analysis	Microglia cell	Association between microglial receptors CD33 and TREM2 in AD, CD33 knockout upregulated genes, including IL-8, attenuating Aβ pathology and improving cognition, while additional TREM2 knockout nullified these effects, suggesting intricate regulation of AD pathology by these receptors.
Wei et al.¹⁰⁴	Immunofluorescence staining, clonal expansion assay, real-time label-free dynamic cell analysis, multiplexed immunohistochemistry, western blotting, Chip-seq	HMC3 and BV2 cells, microglia, and hippocampal tissue cells from APP/PS1 AD mice. Also, C57BL/6 mice were used.	Elevated lactic acid levels and H3K18 lactylation in senescent microglia and hippocampal tissues, activate the NF-κB pathway and upregulate IL-6 and IL-8, suggesting therapeutic potential in targeting the H3K18la/NFκB axis
Bakshi et al.^106,107	ELISA, LC-MS/MS analysis	HEKwt cell line, APP/PS1 mice, CHO cells	CXCR2 stimulation boosts γ-secretase activity, elevating Aβ₁₋₄₂ and Aβ₁₋₄₀ production while depletion of CXCR2 in APP/PS1 mice reduced Aβ levels and increased γ-secretase substrates.
Li et al.⁹⁴	PCR-RFLP		The study aimed to determine if IL-8 -251 T/A and MTHFR 677 C/T—and their combined effect risk in a Chinese population polymorphism is associated with an increased risk of AD and whether this association is influenced by the MTHFR 677 C/T variant, which is known to affect serum homocysteine levels.
Ryu et al.¹¹¹	Western blot, RT-PCR, immunohistochemistry	Postmortem cortical section from Wistar rats	Pharmacological antagonism of CXCR2 using SB332235 significantly reduces inflammatory reactivity in AD animal model
Watson et al. ⁹⁸	TUNEL assay, western blot, immunofluorescence	Primary hippocampal neuronal cell culture	CXCR2 ligands, such as MIP-2, CXCL1, and IL-8, protect hippocampal neurons from Aβ induced death through the activation of MEK1-ERK1/2 and PI3K-Akt signalling pathways.
Zhang et al.¹¹²	Immunohistochemistry, Luminex, western blotting	Hippocampal neuron cell culture from Sprague-Dawley and C57BL/6 mice rat	In long-term cultured neurons, CXCL1, which is a ligand of CXCR2, induces tau cleavage at ASP421 via caspase-3, leading to abnormal tau distribution and structure.
Raman et al.¹¹³	Immunocytochemistry immunohistochemistry, RT-PCR, apoptosis assay, western blotting, neuronal tracing and morphometry, Golgi-Cox staining of neurons	Mixed cerebral cortical and hippocampal neuronal cultures from CXCR2(−/−) mice and CXCR2 (+/+) mice	Chemokines MIP-2 and CXCL12 confer neuroprotection against Aβ-induced neurotoxicity by preventing dendritic regression and neuronal apoptosis through the activation of PI-3-kinase and ERK1/2 pathways
Zhang et al., ¹¹⁴	THP-1; APP/PS1 mice, western blot, flow cytometry, RT-PCR, TEER, and HRP flux measurements, immunofluorescence, plasmid construction and transfection, Rho assay	HBMEC	Monocytes with upregulated CXCL1 interact with CXCR2 on HBMEC, promoting Aβ-induced transendothelial migration, and showed that neutralizing CXCL1 reduces monocyte migration across the blood-brain barrier and accumulation of microglia in AD mouse brains.
Xia et al., ¹¹⁵	Immunohistochemistry and immunostaining, western blotting	Postmortem temporal brain tissues and mouse primary cortical–hippocampal neurons were plated	GROα/KC, a ligand for chemokine receptor CXCR2, significantly activates neuronal ERK1/2 and PI-3 kinase pathways, along with inducing tau hyperphosphorylation in mouse primary cortical neurons

Aβ: amyloid-β; AD: Alzheimer's disease; APP: amyloid-β precursor protein; BDNF: brain-derived neurotrophic factor; CXCR: chemokine receptor type; CSF: cerebrospinal fluid; ELISA: enzyme-linked immunosorbent assay; ERK: extracellular signal-regulated-kinase; FACS: fluorescent-activated cell sorter; HBMECs: human brain microvascular endothelial cells; IL: interleukin; LC–MS/MS: liquid chromatography-mass spectrometry; LPS: lipopolysaccharide; MCP-1: monocyte chemoattractant protein-1; MIP: macrophage inflammatory protein; NF-κB: nuclear factor kappa B; PCR-RFLP, polymerase chain reaction-restriction fragment length polymorphism; RT-PCR: reverse transcription polymerase chain reaction; TGF: transforming growth factor; TNF: tumor necrosis factor.

The initial studies demonstrating the production of IL-8 by resident cells of the central nervous system, particularly by astrocytes and microglia, in response to inflammatory stimuli, date back to the 1990s. Astrocyte-enriched populations derived from the human embryonic brain were demonstrated to produce several cytokines, including IL-8, upon stimulation with TNF-α, and IL-1 β.⁹⁵ The production of IL-8 within the brain was also demonstrated in vitro by the human fetal microglia upon stimulation with lipopolysaccharide (LPS), IL-1 β, and TNF-α. On the contrary, pretreatment with IL-4, IL-10, or transforming growth factor-beta1 (TGF-β1) had an inhibitory effect on this process.¹⁸

Ashutosh et al. confirmed that microglia and astrocytes produce IL-8 upon inflammatory cytokines stimulation, and they also demonstrated that surprisingly neurons are also capable of IL-8 production. These Authors demonstrated for the first time that Aβ upregulates neuronal production of CXCL8 and proposed that neuronal response to Aβ by producing IL-8 could represent a significant step in the pathogenesis of AD.⁹⁶

Ashutosh and colleagues also investigated the direct impact of IL-8 on neurons, which represents a matter of varying interpretations. While some studies have indicated an increase in apoptosis in primary rat neurons upon exposure to IL-8,⁹⁷ contrasting findings have suggested a protective effect of IL-8 in murine neonatal hippocampal neurons.⁹⁸ Additionally, other studies found no discernible effects of IL-8 on cell survival.⁹⁹ IL8 alone was not found to induce cytotoxicity or proliferation in human neurons in vitro by Ashutosh and colleagues. Intriguingly, treatment of human neurons with CXCL8-neutralizing antibodies did not significantly increase apoptosis.¹⁰⁰ The authors proposed that IL-8 may provide neuroprotection through an autocrine mechanism by stimulating the synthesis or release of neurotrophic factors. Thus, they investigated neurotrophic factor release, particularly focusing on brain-derived neurotrophic factor (BDNF). While IL-8 alone did not impact neuronal survival, it did suppress Aβ-induced neuronal apoptosis and enhance BDNF production.⁹⁶

Franciosi et al. investigated the influence of IL-8 on Aβ₁₋₄₂-induced responses in cultured human fetal microglia. Using RT-PCR, ELISA, and immunocytochemistry, the study found that exposure to Aβ₁₋₄₂ led to increased expression and production of pro-inflammatory cytokines IL-1β, TNF-α, IL-6, and IL-8 after eight hours. Moreover, the addition of IL-8 with Aβ₁₋₄₂ further elevated the production of these factors compared to Aβ₁₋₄₂ alone. Interestingly, IL-8 by itself increased the expression of pro-inflammatory cytokines and cyclooxygenase-2 (COX-2) without altering their protein levels, indicating that IL-8 may intensify Aβ₁₋₄₂-induced inflammatory responses in microglia.¹⁰⁰

In a study conducted by Walker et al., gene array profiling of Aβ peptide-stimulated human postmortem brain microglia revealed up/downregulation of 104 genes, with IL-8 exhibiting the highest induction, with expression increased by 11.7-fold at the RNA level.¹⁰¹

In an earlier study, Lih-Fen and colleagues developed and characterized microglia and astrocyte cultures obtained from rapid brain autopsies (less than 4 h postmortem) of patients with AD and nondemented elderly controls. These cultures were sourced from both white matter (corpus callosum) and grey matter (superior frontal gyrus). They found significant, dose-dependent increases in the production of pro-IL-1β, IL-6, TNF-α, MCP-1, macrophage inflammatory protein-1α (MIP-1α), IL-8, and macrophage colony-stimulating factor (M-CSF) following exposure to pre-aggregated Aβ1–42.¹⁰²

Griciuc and colleagues investigated the interplay between microglial receptors CD33 and Triggering receptor expressed on myeloid cells 2 (TREM2) in AD revealing a complex relationship between these receptors in the disease pathogenesis. In this interesting study, these researchers found that genes related to phagocytosis and signalling, including IL-8, were upregulated in mice lacking CD33, which reduced Aβ pathology and improved cognitive abilities. However, these beneficial effects were nullified when TREM2 was additionally knocked out. Conversely, knocking out TREM2 exacerbated Aβ pathology and neurodegeneration but led to a reduction in the number of certain microglial cells, without any rescue by additional CD33 knockout. These results suggest that CD33 and TREM2 may act together to regulate several genes, including IL-8, and this may impact the development of AD pathology.¹⁰³

Additionally, another recent study examining lactic acid levels in senescent microglia and hippocampal tissues of aged and APP/PS1 AD modeling mice found significant elevation compared to controls. Elevated histone lysine lactylation, particularly H3K18 lactylation (H3K18la), was identified in senescent microglia and AD mouse hippocampi, activating the NF-κB pathway and upregulating senescence-associated secretory phenotype (SASP) components IL-6 and IL-8. Targeting the H3K18la/NF-κB axis may offer therapeutic potential in delaying ageing and AD progression by mitigating SASP effects.¹⁰⁴

Boccardi and his colleagues studied a cohort of 80 AD patients and documented lower levels of α-tocopherol, as well as higher levels of G-CSF, GM-CSF, INF-α2, IL-3, and IL-8, and lower levels of IL-17.¹⁰⁵

Studies have shown an upregulation of CXCR2 in senile plaques of dystrophic neuritis.¹⁰¹

Bakshi et al. demonstrated that CXCR2 stimulation enhances γ-secretase activity, thereby increasing the production of Aβ₁₋₄₂ and Aβ₁₋₄₀. However, a direct effect of CXCR2 on γ-secretase was not observed. In detail, a depletion of CXCR2 in CXCR2 knockout mice expressing presenilin (PS1 M146L) and APPsw mutations resulted in reduced levels of Aβ₁₋₄₂ and Aβ₁₋₄₀, along with concurrent increases in γ-secretase substrates. Furthermore, the inhibitory effect of a selective CXCR2 antagonist on Aβ₁₋₄₂ and Aβ₁₋₄₀ was found to be mediated via γ-secretase, specifically through a reduction in the expression of presenilin, a component of the γ-secretase complex. Therefore, these findings shed light on the possible therapeutic role of CXCR2 for AD.^106–109

Liu et al. found that T-cell migration through an in vitro BBB model was effectively inhibited by anti-CXCR2 antibody or IL-8. Specifically, the administration of a competitive CXCR2 antagonist into the rat hippocampus resulted in a gradual decrease in microgliosis, accumulation of T lymphocytes, and oxidative stress, ultimately leading to the alleviation of neuronal loss in the dentate gyrus of Aβ-injected rats.¹¹⁰

Ryu et al. demonstrated that the pharmacological antagonism of CXCR2 effectively attenuates inflammatory reactivity and confers neuroprotection against oxidative damage in an animal model of AD. Using an AD animal model involving intrahippocampal injection of Aβ_1–42 peptide in rats, the researchers found that CXCR2 expression and IL-8 production increased in a time-dependent manner following Aβ_1–42 injection. These modifications were accompanied by enhanced gliosis and reduced neuronal survival. Treatment with the CXCR2 antagonist SB332235 significantly reduced the expression of CXCR2 and microgliosis, while also conferring neuroprotection against Aβ_1–42-induced neuronal loss. Additionally, SB332235 treatment attenuated oxidative stress markers, including lipid peroxidation and superoxide production.¹¹¹

When exploring the role of IL-8 in the pathogenesis of AD, the other ligands of CXCR2 should also be considered.

Watson et al. demonstrated that other CXCR2 ligands, including macrophage inflammatory protein 2 (MIP-2), CXCL1, and CXCL8, protect hippocampal neurons against Aβ₁₋₄₂-induced death.⁹⁹

Zhang et al. demonstrated that CXCL1 induced cleavage of tau at ASP421 in a caspase-3-dependent manner in long-term cultured neurons, but not in short-term cultured neurons. The cleaved tau exhibited an abnormal distribution, forming varicosities or bead-like structures along the neurites, a phenomenon apparently specifically induced by CXCL1 that was not previously observed. They also found that CXCL1-induced activation of glycogen synthase kinase-3β and subsequent tau phosphorylation preceded and were necessary for caspase-3 activation and tau cleavage. Additionally, intrahippocampal microinjection of lentiviral CXCL1 induced tau cleavage specifically in hippocampal neurons in aged mice (15–18 months), but not in adult mice (5–10 months). These findings suggested a novel role of CXCR2 in tau cleavage which represent an important step towards AD pathology.¹¹²

Raman et al. demonstrated the neuroprotective effects of chemokines MIP-2 and CXCL12 against Aβ-induced neurotoxicity. They found that pretreatment with either MIP-2 or CXCL12 significantly prevented dendritic regression and neuronal apoptosis in mouse primary neuronal cultures exposed to Aβ and showed that this process was due to the activation of the PI-3-kinase and ERK1/2 pathways. In their study, the authors also demonstrated that pretreating CXCR2−/− mice with MIP-2 reduced the Aβ-induced dendritic regression more than what was documented in CXCR2+/+ mice, suggesting a role for a different receptor of MIP-2 in this neuroprotective effect. RT PCR analysis revealed a 4-fold elevation of CXCR1 mRNA level in adult CXCR2−/− mice compared to barely detectable levels in CXCR2+/+ mice, suggesting upregulation of the CXCR1 receptor in the absence of CXCR2.¹¹³

Zhang et al. found that AD patients’ monocytes exhibit upregulated expression of CXCL1, which interacts with CXCR2 on human brain microvascular endothelial cells (HBMEC), facilitating Aβ-induced transendothelial migration. Using in vitro and in vivo models, they showed that neutralizing CXCL1 reduces monocyte migration across the BBB and accumulation of bone marrow-derived microglia in AD mouse brains. Additionally, they revealed that Aβ stimulation upregulates CXCR2 expression on HBMEC, promoting CXCL1-mediated monocyte migration. Further investigations indicated that CXCL1-overexpressing monocytes induce tight junction disassembly in HBMEC via Rho/ROCK signalling activation, ultimately enhancing transendothelial migration.¹¹⁴

Xia et al. demonstrated that GROα/KC, another CXCR2 ligand, acts as a potent trigger for neuronal ERK1/2 and PI-3 kinase pathways, as well as tau hyperphosphorylation in mouse primary cortical neurons. They found that GROα immunoreactivity can be detected in a subpopulation of neurons in both normal and AD conditions.¹¹⁵

In conclusion, in vitro investigations held contradictory results, with some studies highlighting the production of IL-8 by various central nervous system cells, its modulation of inflammatory responses, and its potential neuroprotective effects, and other studies suggesting a negative impact of IL-8 on neuronal survival and its exacerbation of Aβ-induced inflammation in microglia. Furthermore, the interplay between IL-8 and other factors such as CXCR2 ligands suggests intricate signalling networks that need better elucidation in future studies (Table 1).

IL-8 in AD patients

Numerous studies have explored cytokine concentrations in biofluids of AD and MCI patients, including IL-8. However, whether the levels of IL-8 are elevated in the biofluids of AD patients is still a matter of debate and the studies conducted thus far are limited by several factors, including study design, the disease stage at which patients are examined, sample size, and the scarcity of longitudinal data. The main findings of these studies are summarized in Table 2.

Table 2.

Main evidence from human studies.

Reference	Methods	Matrix	Main Findings
Boccardi et al.¹⁰⁵	Multiplex biometric ELISA-based immunoassay, HPLC, RT-PCR	Plasma	Lower levels of α-tocopherol, higher levels of certain inflammatory cytokines, and downregulated miRNAs, with miR-122 showing a positive correlation with both inflammatory molecules and α-tocopherol
Galimberti et al.²⁰	ELISA, RT-PCR	CSF	Elevated MCP-1 and IL-8 levels in amnestic MCI and all AD patients CSF correlate positively with age, while IP-10 was only significantly elevated in MCI and mild AD cases.
Sokolova et al.¹¹⁶	Bio-Plex assay kit	Tissue from the inferior temporal cortex	Cytokine concentrations in brain tissue extracts from AD patients and controls confirmed the upregulation of IL-8, MCP-1, and IL-6, localizing IL-8 in neurons, astrocytes, and plaques.
Alsadany et al.⁶⁹	ELISA, HDAC assay, MMSE	Plasma	Elevated plasma levels of IL-8 in AD patients compared to healthy elderly subjects.
Doroszkiewicz et al.¹¹⁷	Immunoenzyme assays.	CSF	Elevated IL-8 concentrations in AD patients compared to non-demented controls, correlating with other AD biomarkers including Aβ₄₂/Aβ₄₀ ratio, tau, and pTau181.
Zhang et al.¹¹⁸	Immunobead-based multiplex assay	CSF	CSF concentrations of IL-8 using in AD, Parkinson's disease patients, and healthy controls, observe elevated levels of this cytokine in both neurodegenerative diseases.
Aksnes et al.¹¹⁹	Multiplex assay, ThT-FCS assay	Serum	Higher serum IL-8 levels in AD patients compared to non-AD patients.
Swardfager et al.¹²⁰	Peer-reviewed studies, Meta analysis	NA	A 2010 meta-analysis found no significant difference in IL-8 levels between AD patients and controls.
Zuliani et al.¹²¹	ELISA	Plasma	Found no disparity in plasma IL-8 concentrations between LOAD and vascular dementia patients compared to controls.
Kim et al.⁸⁴	MMSE, BioPlex cytokine assay, ELISA	Plasma	Decreased level of IL-8 in a cohort of MCI and AD patients
Hesse et al.¹²²	Multiplex electrochemiluminescence assay	Serum	Low CSF and serum IL-8 levels were observed in AD patients compared to controls.
Capogna et al.¹²³	MRI, MSD, ELISA, multiplex immunoassay	CSF	A long-term study found that the relationship between IL-6 and IL-8 concentrations in CSF increased with age and AD, with higher CSF IL-8 levels correlating with better memory performance.
Bruno et al.¹²⁴	ELISA	CSF	Higher levels of IL-4 and IL-8 correlated with increased BBB permeability, while elevated levels of MIP-1β and TNF-α were associated with decreased permeability, with age also positively correlating with BBB permeability
Zhu et al.⁸¹	Multiplex xMAP-based Luminex assays	Serum	Significant upregulation of microglial activation-related genes, including IL-8, alongside downregulation of others within Aβ plaques in AD.
Foley et al¹⁰⁸	SIMOA-based protein assay	Plasma	Correlation between AD-associated protein biomarkers and inflammatory biomarkers in plasma, finding significant associations between them.
Vaz et al.¹⁰⁹	SH-SY5Y cells, western blotting, flow cytometry	Plasma	SH-SY5Y cells exposed to IL-8 and MCP-1, observed an increase in tau phosphorylation, leading to the formation of neurofibrillary tangles. Tau phosphorylation correlates with the inhibition of PPs activity and GSK-3β phosphorylation. Also, followed up with plasma IL-8 levels in individuals with cognitive deficits and observed decreased IL-8 levels.
Xia et al.¹²⁵	Postmortem brain tissue from temporal lobes, Immunohistochemistry	Postmortem brain tissue from temporal lobes	Presence of IL-8/CXCR2 in AD brains, observing its expression in swollen dystrophic neurites of neuritic plaques, hinting at its involvement in neuronal-glial interactions.
Horuk et al.¹²⁶	Immunohistochemistry	Tissue from neuritic portion of plaques surrounding deposits of amyloid from AD patients	Presence of CXCR2 expression within neuritic plaques, especially in regions surrounding amyloid deposits.
Ryu et al. ¹¹¹	AD animal/rat model incorporating injection of full-length Aβ₁₋₄₂ into rat hippocampus. Immunohistochemistry, western blot, RT-PCR	Postmortem tissue from cortical section	Elevated CXCR2 expression levels in AD brains compared to non-demented patients
Gertje et al.¹²⁷	Cell culture, small interfering RNAs for CXCR2	CSF	In non-demented individuals was found that higher levels of IL-8 and vascular injury markers in cerebrospinal fluid were linked to increased WML volume, and cognitive decline over time.
Liu et al.¹¹⁰	AD animal/rat model, HBMEC cells, BV2 cells, RNAi in HBMECs.RT-PCR, immunofluorescence, western blot, ELISA	Serum	Inhibition of T-cell migration using anti-CXCR2 antibody, and administration of a CXCR2 antagonist via Aβ injection into rat hippocampus reduced microgliosis, T lymphocyte accumulation, oxidative stress, and neuronal loss in the dentate gyrus.
Araújo et al.¹²⁸	Machine-learning based blood panel	NA	Machine learning-based blood panel predicting AD progression from MCI to dementia, revealing 12 plasma proteins as potential biomarkers

Aβ: amyloid-β; AD: Alzheimer's disease; BBB: blood-brain barrier; CSF: cerebrospinal fluid; CXCL: chemokine (C-X-C motif) ligand; ELISA: enzyme-linked immunosorbent assay; HBMECs: human brain microvascular endothelial cells; HADC: histone deacetylase assay; HPLC: high-performance liquid chromatography; IL: interleukin; LOAD: late-onset Alzheimer's disease; MCI: mild cognitive impairment; MCP-1: monocyte chemoattractant protein-1; MIP: macrophage inflammatory protein; MMSE: Mini-Mental State Examination; MRI: magnetic resonance imaging; MSD: mesoscale discovery test; PPs: protein phosphatases; RNAi: RNA interference; RT-PCR: reverse transcription polymerase chain reaction; SIMOA: single molecule assay; ThT-FCS: thioflavin-T fluorescence correlation spectroscopy assay; TNF: tumor necrosis factor

Galimberti and colleagues assessed the levels of IP-10, MCP-1, and IL-8 in CSF of individuals with amnestic MCI and AD compared to age-matched controls. They found that IP-10 was significantly elevated in MCI and mild AD patients, but not in severe AD cases, while MCP-1 and IL-8 levels were increased in MCI and all AD patients. Remarkably, MCP-1 and IL-8 levels correlated positively with age.²⁰

Sokolova and colleagues investigated the cytokine concentrations using a Bio-Plex bead-based immunoassay kit in brain tissue extracts from 10 controls and from 12 patients with and without genetic forms of AD. In the same cohorts of patients, they also performed the immunohistochemical analysis on 10-µm-thick sections cut from paraffin-embedded formalin-fixed tissue blocks of the inferior temporal association cortex. IL-8, together with MCP-1 and IL-6 were found to be consistently upregulated in the brain tissue of AD patients, and this was confirmed with immunohistochemistry which showed that the IL-8 localizes in neurons, astrocytes, and plaques.¹¹⁶

Alsadany and colleagues assessed the plasma levels of IL-8 in 25 AD patients compared with 25 cognitively normal, healthy elderly subjects. They found increased plasma concentrations of this cytokine in AD patients than control participants.⁶⁹

In another study, Doroszkiewicz and colleagues revealed significantly higher IL-8 concentrations in AD patients compared to non-demented controls, and these elevated levels correlated with other AD biomarkers such as Aβ₄₂/Aβ₄₀ ratio, Tau, and pTau181.¹¹⁷

Zhang and colleagues assessed the CSF concentrations of IL-8 with an immunobead-based multiplex assay in different cohorts of AD, Parkinson's disease patients, and a cohort of healthy controls and found increased levels of this cytokine in both these neurodegenerative diseases.¹¹⁸

A recent study assessed the serum levels of several cytokines, including IL-8 with a multiplex assay in 49 patients followed for cognitive complaints at the Oslo University Hospital Memory Clinic (15 with clinical AD) and found increased levels of IL-8 in patients with clinical AD compared to non-AD patients.¹¹⁹ On the contrary, a meta-analysis performed in 2010, including original English-language peer-reviewed studies assessing cytokine concentrations in AD and healthy control subjects, did not find any significant difference in CSF or peripheral blood IL-8 concentrations in patients affected by AD.¹²⁰

Zuliani and colleagues investigated the plasma levels of different cytokines, including IL-8 in a cohort of late-onset AD and vascular dementia patients, with an ELISA approach. They did not find any difference in IL-8 plasma concentrations comparing late-onset AD and vascular dementia patients to the controls. Moreover, no correlation was found between IL-8 plasma levels and functional status of the patients.¹²¹

Surprisingly, Kim and colleagues described a decreased level of IL-8 in a cohort of MCI and AD patients from the Ansan Geriatric Study (AGE study).⁸⁴ These results are similar to those reported by Hesse and colleagues, studying the role of pro-inflammatory cytokines, IL-1β, IL-8, and TNF-α, in serum and CSF samples from AD patients and control subjects using a multiplex electrochemiluminescence assay. The authors revealed significantly lower levels of both CSF and serum IL-8 in AD patients compared to controls.¹²²

A longitudinal study, spanning up to 9 years, demonstrated that the CSF concentrations of IL-6 and IL-8 increased with age and in AD patients. Higher CSF IL-8 levels were associated with better memory performance over time, particularly in individuals with lower CSF p-Tau levels, suggesting a potential neuroprotective role for IL-8 and IL-6 in cognitively healthy older adults with a lower load of AD pathology.¹²³

Bruno et al. examined the association between BBB permeability and neuroinflammation in AD patients using CSF/plasma albumin quotient as a measure of BBB permeability. Fifty-nine patients MCI or early AD were analyzed for CSF inflammatory cytokine levels with ELISA. The results showed that higher levels of IL-4 and IL-8, as well as the age, were associated with increased BBB permeability. These findings support the idea that BBB integrity may influence or be influenced by central neuroinflammation, aligning with previous studies indicating a link between BBB status and neurodegeneration.¹²⁴

Following studies, showed significant upregulation of genes involved in microglial activation, including IL-8, alongside downregulation of others within Aβ plaques in AD.⁸¹ Furthermore, Foley and colleagues investigated the correlation between protein biomarkers associated with AD and inflammatory biomarkers present in plasma. Analysis of 837 plasma samples revealed significant associations between AD-related biomarkers (Aβ₄₀, Aβ₄₂, Aβ_42/40, p-tau181, total tau, and NfL) and inflammatory biomarkers, (TNF-α, IL-6, IL-8, IL-10, and GFAP), suggesting peripheral inflammatory interactions with increasing AD pathology and potentially opening new avenues for diagnosis and treatment monitoring in AD.¹⁰⁸

Xia and colleagues studied the expression of CXCR2 in AD brains and found that immunoreactivity was detected in swollen dystrophic neurites of neuritic plaques in AD brains, suggesting a potential role for this receptor in mediating neuronal-glial interactions.¹²⁵ Remarkably, also another study demonstrated the expression of CXCR2 in neuritic plaques, particularly in the portion of plaques surrounding the deposits of amyloid.¹²⁶

In the study by Ryu and colleagues, immunohistochemical analysis of human AD brain tissue revealed elevated expression of CXCR2, particularly in microglia, implicating CXCR2 as a potential inflammatory mediator in AD progression.¹¹¹ In another study, they investigated the relationship between white matter lesions (WML), indicative of small vessel disease, and CSF biomarkers of neuroinflammation in individuals without dementia, finding associations between higher levels of IL-8 and markers of vascular injury (like placental growth factor) with increased WML volumes. Additionally, cognitive decline over time was associated with both neuroinflammatory markers and WML, particularly in those without cognitive impairment at baseline, suggesting that IL-8 may be involved in the development of vascular lesions characterizing WML.¹²⁷ To confirm these findings, they performed a subsequent cross-sectional study that showed that higher serum IL-8 concentrations were associated with cognitive impairment with or without dementia only in the presence of significant white-matter hyperintensities in the context of cerebrovascular disease.¹¹⁰

Finally, another study identified 12 plasma proteins (ApoB, Calcitonin, C-peptide, CRP, IGFBP-2, IL-3, IL-8, PARC, Serotransferrin, THP, TLSP 1-309, and TN-C), including IL-8, as predictive biomarkers of AD progression from MCI to full dementia¹²⁸ (Table 2).

Key concepts:

- IL-8 production by CNS cells: In vitro studies demonstrate that IL-8 is produced by CNS cells, including astrocytes, microglia, and neurons, in response to inflammatory stimuli such as TNF-α and Aβ, contributing to AD pathology.

- Contradictory effects on neurons: The impact of IL-8 on neurons is debated, with studies showing both neuroprotective effects through mechanisms such as increased BDNF production and detrimental effects such as increased apoptosis and exacerbation of Aβ-induced inflammation.

Future directions

Ongoing investigations centered on the evidence in discovering AD biomarkers relates to the role of neuroinflammation in neurodegeneration. Current evidence suggests that neutrophils may significantly contribute to increased neuroinflammation and compromise the BBB, potentially influencing cognitive decline in individuals with AD. Despite numerous findings indicating the presence of neutrophils in AD brain, the exact characterization of their role in AD development remains understudied.¹²⁹

A first-in-class drug has created a pan-ELR + CXC chemokine blocking monoclonal antibody that antagonizes CXCR receptors in cancer patients. LY30416588 is a humanized blockade of all seven subunits (CXCL1, 23,5-8) for the chemokines expressed in humans. CUG-2584 does inhibits ELR + CXC chemokine-induced Ca2 + mobilization, CXCR2 internalization and chemotaxis in vitro as well as neutrophil movement in vivo.¹³⁰

In another study, Tran and colleagues used the LY3041658/IL-8 complex as a target to identify potential small molecule inhibitors of IL-8 using computational methods. Results indicated ZINC21882765 as the best potential inhibitor of IL-8, suggesting it could effectively block IL-8 and its receptors, with potential therapeutic implications for conditions where IL-8 plays a critical role, such as severe COVID-19.¹³¹

Notably, IL-8 represents a pivotal cytokine in neutrophil recruitment and the understanding of its role in AD pathogenesis and progression is still in its early stages. The complex interplay between the recruitment of activated microglia to sites of brain damage and the elevated detection levels of IL-8 in the serum of AD patients suggests that studying the dynamics of IL-8 expression and its correlation with disease severity could provide valuable insights. These insights could enhance the utility of neuroinflammatory biomarkers, including IL-8 for disease progression and may suggest possible new therapeutic targets for AD.

Conclusions

The evidence collected thus far underscores the critical role of IL-8 in AD patients. IL-8 appears to impact the recruitment of activated microglia to sites of brain damage, thereby contributing to enhanced neuroinflammatory activity. Understanding the role of IL-8 in neuroinflammation and AD progression is crucial for developing effective diagnostic and therapeutic strategies.

Footnotes

Acknowledgments

The authors have no acknowledgments to report.

ORCID iDs

Delia Righi

Carlo Manco

Angela Stufano

Domenico Plantone

Author contributions

Delia Righi (Conceptualization; Formal analysis; Investigation; Methodology); Carlo Manco (Resources); Matteo Pardini (Supervision); Angela Stufano (Conceptualization; Supervision); Valentina Schino (Resources); Virginia Pelagotti (Resources); Federico Massa (Resources; Visualization); Nicola De Stefano (Validation); Domenico Plantone (Conceptualization; Formal analysis; Investigation; Methodology).

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability

The data supporting the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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