Guardians of the Lung: The Multifaceted Roles of Macrophages in Cancer and Infectious Disease

Abstract

The lung as an organ that is fully exposed to the external environment for extended periods, comes into contact with numerous inhaled microorganisms. Lung macrophages are crucial for maintaining lung immunity and operate primarily through signaling pathways such as toll-like receptor 4 and nuclear factor-κB pathways. These macrophages constitute a diverse population with significant plasticity, exhibiting different phenotypes and functions on the basis of their origin, tissue residence, and environmental factors. During lung homeostasis, they are involved in the clearance of inhaled particles, cellular remnants, and even participate in metabolic processes. In disease states, lung macrophages transition from the inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. These distinct phenotypes have varying transcriptional profiles and serve different functions, from combating pathogens to repairing inflammation-induced damage. However, macrophages can also exacerbate lung injury during prolonged inflammation or exposure to antigens. In this review, we delve into the diverse roles of pulmonary macrophages the realms in homeostasis, pneumonia, tuberculosis, and lung tumors.

Introduction

Macrophages play a primary role in engulfing and removing cellular debris, foreign substances, microorganisms, and cancer cells. Present in various organs, they contribute significantly to tissue homeostasis (Xu et al., 2022). Pulmonary macrophages can secrete a variety of cytokines to activate toll-like receptor 4 (TLR4), nuclear factor-κB (NF-κB), and other pathways (Rossol et al., 2011). Within the lung, these macrophages are essential for organogenesis, preserving equilibrium, tissue regeneration, and orchestrating immune surveillance against intruders while maintaining tolerance toward noninflammatory cues (Garbi and Lambrecht, 2017). Pulmonary macrophages serve to protect the lungs by engulfing inhaled particles, pathogens, apoptotic cells, and cellular remnants, triggering an inflammatory response, generating proinflammatory factors, and facilitating cell recruitment. Conversely, they also partake in producing anti-inflammatory factors and engaging in phagocytosis of apoptotic cells, which are central to resolving inflammation (Fujiwara and Kobayashi, 2005). In the context of pulmonary tuberculosis (TB), pulmonary macrophages have a dual role, serving as preferred hiding and replication sites for Mycobacterium tuberculosis (MTB) while also exhibiting antibacterial functions (Leemans et al., 2005). Furthermore, during tumor development, tumor-associated macrophages (TAMs) demonstrate a dual functionality by producing inflammatory mediators and cytotoxic substances to exert immune and antitumor effects, as well as generating proinflammatory factors and growth factors that suppress immunity and promote tumor growth (Yang et al., 2020). This review aims to offer a concise delineation of the phenotype and function of lung macrophages within the realms of homeostasis, inflammatory lung diseases, TB, and lung tumors.

Classification and Function of Pulmonary Macrophages

Macrophages are myeloid immune cells that are distributed throughout the body’s tissues. They are unable to self-renew or may perish during infections, and are subsequently replaced by monocytes that differentiate into macrophages. Within the connective tissue, these mononuclear cells undergo volumetric expansion, leading to the proliferation of endoplasmic reticulum, mitochondria, lysosomes, and intensified phagocytic capabilities (Coillard and Segura, 2019). Macrophages are not confined solely to the circulatory system, they are distributed throughout the body, exhibiting varying names and forms depending on their specific locations (Blériot et al., 2020). In the pulmonary region, macrophages can be broadly categorized based on their anatomical distribution into two main groups: alveolar macrophages (AMs) and interstitial macrophages (IMs) (Aegerter et al., 2022). AMs are situated in the alveolar cavities, characterized by extended longevity and a low turnover rate (Woo et al., 2021). Conversely, IMs are predominantly found in the alveolar interstitium, bronchial submucosa, and adventitia, displaying a shorter lifespan and a faster renewal rate (Schyns et al., 2018). Furthermore, based on their fundamental functions and activation levels, macrophages can be divided into M1 and M2 types (shown in Table 1) (Strizova et al., 2023; Liu et al., 2022b). M1 macrophages serve as the primary proinflammatory macrophages, and the M2 macrophages encompass several subtypes (Shen et al., 2023). For instance, M2a macrophages primarily promote fibrosis and tissue regeneration (Tang et al., 2017; Huang et al., 2024), M2b macrophages contribute to immune responses regulation and inflammation (Wang et al., 2019), and M2c macrophages aid in phagocytosis, possess anti-inflammatory properties, and contribute to fibrosis (Tang et al., 2017). In addition, M2d macrophages are implicated in promoting tumor angiogenesis and metastasis (Wang et al., 2010). Macrophages exhibit plasticity, enabling them to adjust their physiological roles in accordance with various stimuli as needed. Given the continuous exposure of the lungs to the external milieu during the breathing process, numerous factors can modulate macrophage gene transcription, thereby influencing their phenotype and function (Locati et al., 2020).

Table 1.

Classification and Functions of Macrophages

Classification	Activating factor	Function
M1	LPS, IFN-γ	Promotes inflammatory response
M2a	IL-4, IL-13	Inhibiting the inflammatory response; promoting tissue repair
M2b	IC, LPS, IL-1β	Immune regulation; promote infection; promoting tumor progression
M2c	IL-10, TGF-β	Immune suppression; cell phagocytosis; tissue remodeling
M2d	LPS, IL-6	Promote tumor progression and angiogenesis.

LPS, lipopolysaccharide; IL, interleukin; IFN, interferon; TGF, transforming growth factor.

Currently, there exist three recognized origins of pulmonary macrophages: mesodermal progenitor cells from the yolk sac during embryonic stage, bone marrow-derived cells, and cells originating from adjacent tissues (Gomez Perdiguero et al., 2015; Loos et al., 2023). These pulmonary macrophages contribute to eliminating residual tissues such as placental and amniotic remnants both in the fetal period and postnatally, while also contributing to the normal development of the lungs. They have the ability to release growth factors and cytokines, supporting the healthy maturation of alveoli and blood vessels, thereby upholding the structural integrity and functional stability of the lungs (Yu et al., 2017). In instances of lung tissue damage, macrophages have the capacity to secrete growth factors, including insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor-alpha (VEGF-α), and transforming growth factor-beta (TGF-β), which govern epithelial and endothelial cell proliferation, myofibroblast cell activation, vascular stem cell, and tissue differentiation, thereby facilitating tissue regeneration (Vannella and Wynn, 2017; Cheng et al., 2021). During periods of homeostasis, macrophages from distinct locales primarily focus on clearing cellular debris and processing blood to recycle essential components required for hemoglobin and heme iron synthesis (Park et al., 2022). AMs as innate immune cells abundant in the alveolar space, participate in regulating the immune response by secreting various cytokines. On one hand, they can secrete interleukin 1 (IL-1), IL-6, and tumor necrosis factor (TNF) to stimulate the body’s inflammatory reactions; on the other hand, they have the capacity to release IL-10 and TGF-β to modulate inflammation and prevent tissue damage (Poor and Morales-Nebreda, 2023). AMs are the primary cells tasked with engulfing inhaled particulate matter and capturing antigens for transport to the draining lymph nodes. Nevertheless, due to their restricted expression of costimulatory molecules, these local cells are not proficient at presenting antigens to T cells, which aids in the facilitation of tolerance responses (Allard et al., 2018). The effective functioning of macrophage cell immune function relies not only on their individual impact but also on the maintenance of a stable environment in the AMs within the lungs. Research indicates that the interaction between AMs and alveolar epithelial type 2 (AEC2) is pivotal in adjusting the production and clearance of lung surfactant, as they engage in capturing and metabolizing surfactants to uphold lung biomechanics (Huang et al., 2023). Lipids and proteins, which make up surfactants, are found in the alveolar space where they function to reduce surface tension and avoid collapse of the alveoli. Dysfunction of AMs can lead to pulmonary surfactant deposition, which may cause respiratory failure (Huang et al., 2023; Kelly and McCarthy, 2020). IMs are less prevalent in the lungs and possess relatively lower potency. However, IMs can effectively phagocytose pathogens and particles, serving as a secondary line of defense against intruders (Shi et al., 2021). Notably, IMs exhibit a smaller morphology and higher expression of human leukocyte antigen DR compared with AMs (Hoppstädter et al., 2010). Under homeostatic conditions, IMs demonstrate immunomodulatory properties owing to the presence of cytokines, including IL-10, IL-6, and IL-1 (Melo et al., 2021).

Signaling Pathways

TLR4 pathway

TLRs represent a crucial class of protein molecules that participate in nonspecific immunity, connecting the nonspecific immunity and adaptive immunity (Kawai and Akira, 2006). TLRs are distributed in various cells, with the main expression in white blood cells being TLR1, TLR2, TLR3, and TLR4 (Takeda and Akira, 2015). TLR4 is distinctive among the TLRs because it can activate signal transduction from both the cell surface and intracellular sources (Lu et al., 2008). The cell surface TLR4 transmits signals through myeloid differentiation primary response 88 (MyD88)-dependent and MyD88-independent pathways, culminating in the secretion of inflammatory factors and type 1 interferon (IFN-1) (shown in Fig. 1) (Ciesielska et al., 2021; Liu et al., 2020). Common bacterial components that can trigger inflammatory responses include lipopolysaccharide (LPS), lipoarabinomannan, peptidoglycan, bacterial lipoproteins, and lipoteichoic acid (Takeuchi and Akira, 2001). Lipopolysaccharide-binding protein facilitates the extraction of LPS and transports it to the cell membrane for binding with TLR4 (Schröder and Schumann, 2005). After binding to LPS, the cell surface TLR 4 recruits multiple linker proteins through Toll/interleukin-1 receptor (TIR) domain. These adapter proteins include MyD88, TIR domain-containing adapter inducing IFN-beta (TRIF), TIR domain-containing adapter (TIRAP), sterile alpha and HEAT-Armadillo motifs (SARM) containing the sterile and armadillo motifs, TRIF-related adaptor molecule (TRAM), TNF receptor-associated factor 6 (TRAF6), and serine-threonine kinase, interleukin-1 receptor-associated kinase (IRAK) (O’Neill and Bowie, 2007). Accessory molecules such as CD 14, CD 36, and myeloid differentiation factor 2 (MD2) can further accelerate TLR 4 immune signal transduction (Huang et al., 2022). CD14 facilitates the interaction between LPS and the TLR4/MD2 receptor complex, where MD2 is an auxiliary protein of TLR4 that enhances the recognition of LPS by binding to TLR4 (Jagtap et al., 2020).The TLR4-MyD88 pathway involves a complex comprising MyD88, phosphorylated IRAK, and TRAF 6, activating transcription factors, NFκB and mitogen-activated protein kinase (MAPK) to induce the production of various inflammatory factors (Pereira et al., 2022). Upon TLR4 activation, MyD88 binds to form the TLR4-MyD88 complex. After the complex is formed, IRAK1 and IRAK4 are activated, leading to the activation of TRAF6. Subsequently, TRAF6 binds to transforming growth factor beta-activated kinase 1 (TAK1)-binding protein 2 (TAB2), thereby recruiting and activating TAK1. Activated TAK1 completes ubiquitination through UBC13 and UEV1A, and further activates IkappaB (IκB) kinase (IKK) through the MEKK3 kinase pathway. Activated IKK can phosphorylate IκB, prompting its degradation, which cause the liberation and translocation of NF-κB into the nucleus (Lu et al., 2008; Pereira et al., 2022). Conversely, MyD88-independent TRIF-mediated TLR4 signaling through the activation of transcription factors, interferon regulatory factor 3 (IRF3) and signal transducer and activator of transcription 1 (STAT1), causing the production of IFN-β, IL-10, and regulated upon activation, normally T-cell expressed, and presumably secreted (RANTES) (Ciesielska et al., 2021; Yamamoto et al., 2003). TLR4 initiates the activation of TRAF3 by interacting with TRAM and TRIF, forming a complex with TRIF, receptor-interacting protein 1, and TRAF3. TRAF3 modulates the activity of TRAF family member-associated NF-κB activator (TANK) binding kinase-1 (TBK1) and IKKi, facilitating the phosphorylation and transposition of IRF3, hence causing the release of interferons (Lu et al., 2008; Güney Eskiler et al., 2019). Both pathways propagate simultaneously on the plasma membrane, but investigations have shown that TRAM-TRIF signaling can be initiated after TLR 4 endocytosis (Takeda and Akira, 2004). Endocytosis of TLR 4 can sense cytosolic LPS to induce NFκB and IRF3-mediated transcription, which is crucial for the complete regulation of innate immunity. Studies indicate that p120-catenin containing armadillo repeat domains, enhances the endocytosis of TLR4 in macrophages and triggers TRIF, thereby activating transcription factor IRF 3 and enhancing the expression of IFN-1 (Yang et al., 2014).

FIG. 1.

TLR4-NFκB signaling pathway. Common bacterial components that can trigger inflammatory responses include LPS, LAM, PGN, BLP, and LTA. LBP facilitates the extraction of LPS from the bacterial surface and transports it to the cell membrane for binding with TLR4. CD14 promotes the formation of the LPS-TLR4/MD2 complex, where MD2 serves as a cofactor for TLR4, enhancing LPS recognition by binding to TLR4. TLR4 can activate both MyD88-dependent and MyD88-independent pathways. Activation of TLR4 result in the formation of the TLR4-MyD88 complex, which in turn activates IRAK1 and IRAK4, causing the activation of the TRAF6 protein. Subsequently, TRAF6 binds with TAB2, recruiting and activating TAK1. TAK1 then undergoes ubiquitination through UBC13 and UEV1A, leading to the activation of IKK, which further phosphorylates IκB. This phosphorylation results in the degradation of IκB, releasing NF-κB to translocate into the cell nucleus. In addition, TLR4 initiates the activation of TRAF3 by interacting with TRAM and TRIF, forming a complex with TRIF, RIP-1, and TRAF3. TRAF3 modulates the activity of TBK1 and IKKI, facilitating the phosphorylation of IRF3 and its translocation into the cell nucleus, hence leading to the release of interferons. By Figdraw. LPS, lipopolysaccharide; BLP, bacterial lipoproteins; PGN, peptidoglycan; LAM, lipoarabinomannan; TLR, toll-like receptor; IRAK, interleukin-1 receptor-associated kinase; TRAF, TNF receptor-associated factor; TRAM, TRIF-related adaptor molecule; RIP-1, receptor-interacting protein 1.

NF-κB pathway

NF-κB is usually in an inactive state, bound with IκB protein to prevent its nuclear translocation, and its activity is influenced by a series of regulatory mechanisms, including the classical and nonclassical pathways (Mulero et al., 2019). The nonclassical pathway mainly involves the processing and activation of p100 (also known as NF-κB2). In the unstimulated state, p100 maintains the inactivity of the NF-κB2/RelB complex through its C-terminal. When specific stimuli [such as lymphotoxin Beta Receptor (LTβR) activation] are received, p100 undergoes partial degradation to generate p52, releasing the NF-κB2/RelB complex and translocating it to the nucleus to participate in the transcription of genes, regulating immune response and cell proliferation (Mulero et al., 2019; Sun, 2012). In the classical pathway, when pulmonary macrophages are triggered by inflammatory factors, bacteria, or viruses, it activates IKK, causing the phosphorylation and degradation of IκB, thereby releasing NF-κB. Activated NF-κB enters the nucleus and regulates the transcription of various genes, including inflammatory mediators, and antiapoptotic proteins (Mulero et al., 2019; Napetschnig and Wu, 2013). Although the nonclassical pathway holds significance, particularly in lymphoid organ development, our focus will be on the classical pathway because it is the main pathway initiated by inflammatory cytokine or pattern recognition receptors (PRRs) after engagement. The classical NF-κB signaling exhibits rapid kinetics compared to the nonclassical signaling, rendering it crucial in the swift innate immune response of frontline cells such as macrophages (Hayden and Ghosh, 2011). When pathogens are recognized by PRRs (such as TLR 4), they signal through MyD88 to initiate NF-κB pathway and subsequent cytokine production (shown in Fig. 1) (Hu et al., 2016). NF-κB can promotes the production of inflammatory mediators such as TNF-α, IL-1β, IL-6, which can attract immune cells to the site of inflammation, bolstering the overall inflammatory response (Mussbacher et al., 2023; Lawrence, 2009). It also regulates the immune, including facilitating macrophage recognition and processing of antigens, well as the activation and proliferation of lymphocytes (Dev et al., 2011; Sasaki and Iwai, 2016; Voisin and Grinberg-Bleyer, 2021). Furthermore, NF-κB exerts influence over cell survival and apoptosis by regulating the expression of apoptosis-related genes (Lin et al., 1999). In some cases, it is considered as a suppressor of apoptosis, safeguarding cells from programmed cell death by upregulating antiapoptotic genes, but dysregulated NF-κB signaling is implicated in the pathogenesis of the majority of malignancies (Verzella et al., 2020). Ubiquitin-specific protease 5 (USP5) is capable of modulating the ubiquitination levels of key proteins in the NF-κB pathway, influencing the activation of this pathway and the expression of downstream genes, thus promoting cancer cell resistance. Therefore, USP5 may a potential target for cancer therapy (Yu et al., 2023). NF-κB assumes a cell-protective role by regulating the expression of genes related to antioxidant stress response and DNA repair mechanisms, thereby mitigating the detrimental effects of external insults on cellular integrity (Mussbacher et al., 2023). In macrophages, the signaling transduction of NF-κB adheres to several principles elucidated in fibroblasts, albeit with some distinctive features. Notably, the significance of c-Rel within the NF-κB dimer is heightened in macrophages, whereas RelA/p50 dimers dominate in fibroblasts (Dorrington and Fraser, 2019). c-Rel is the key of the transcriptional regulation of IL-12 p40 and is involved in resolving inflammation by controlling the enzyme crucial for melatonin synthesis (Sanjabi et al., 2000; Muxel et al., 2012). Moreover, deficiency in c-Rel and p50 proteins can impair the innate immune response, leading to diminished phagocytic activity, bactericidal function, and antimicrobial production in macrophages (Miraghazadeh and Cook, 2018). c-Rel is a crucial element within the NF-κB-activating transcription factor 3 (ATF3)-CCAAT/enhancer binding protein delta (C/EBPδ) transcriptional network in macrophages, enabling them to modulate their inflammatory response in accordance with both transient and prolonged TLR 4 stimulation. This circuit prevents an excessive inflammatory response to relatively minor LPS challenges (Litvak et al., 2009). It is also worth noting that even the influence of specific proteins on gene expression may not be uniform across all macrophages. For instance, the impact of c-Rel on gene expression could vary depending on whether macrophages tissue-resident or recruited from the bloodstream (Grigoriadis et al., 1996). Thus, when anticipating the consequences of NF-κB signaling, it is imperative to take into account the entire biological context in which the signaling process unfolds (Dorrington and Fraser, 2019).

Pulmonary Macrophages in Inflammation

The unique respiratory function of the lungs makes them susceptible to tissue damage from various harmful factors in the external environment. During the initial phase of lung injury, resident AMs and monocytes recruited to the circulation differentiate into proinflammatory cells, promoting inflammatory reactions to clear pathogenic microorganisms and other harmful substances. However, uncontrolled inflammatory reactions can exacerbate tissue damage and hamper lung regeneration (Lee et al., 2021). In the late stage of lung injury, macrophages differentiate into anti-inflammatory cells, suppressing inflammatory reactions and activating AEC2 as progenitor cells for AEC1, which undergo self-renewal and mature to promote tissue regeneration (Lechner et al., 2017).

After invasion of pathogenic microorganisms into the lungs, the pathogen-associated molecular pattern molecules (PAMPs) on their surface can be recognized by resident macrophages in the lungs, such as AMs and IMs, through PRRs such as TLR4. This recognition further activates nuclear transcription factors including NF-κB, IFN regulatory factor (IRF), STAT, initiating various pathways and triggering the transcription and synthesis of multiple cytokines such as TNF-α, IL-6, and IL-1β (shown in Fig. 2) (Zhang et al., 2021a; Le et al., 2023; Weiden et al., 2000). After the secretion of these cytokines, circulating monocytes and neutrophils are further recruited to the lungs, which play a role in killing and clearing pathogenic microorganisms through the production of nitric oxide and neutrophil extracellular traps (Zou et al., 2023). Macrophages serve as the primary inflammatory cells that drive the amplification of inflammation responses. Their surface activation markers include CD86 and CD83, among others, which may also be associated with the severity and prognosis of inflammatory diseases (Nicod et al., 2005). For instance, the macrophage mannose receptor CD206 can potentially prognosticate the outcome of community-acquired pneumonia, with the serum levels of sCD206 exhibiting a positive association with disease severity (Tsuchiya et al., 2019). In addition, after macrophages phagocytose pathogens, they integrate the pathogenic antigens into the cell membrane and attach them to major histocompatibility complex class II (MHCII) molecules, presenting them to the corresponding helper T cells to initiate cellular immunity (Guerriero, 2019). Therefore, a certain degree of inflammatory response is an important defense mechanism of the body against various infections and helps protect the body from damage caused by invasive pathogenic microorganisms (Poor and Morales-Nebreda, 2023). However, if this inflammatory response is not effectively inhibited by endogenous and exogenous anti-inflammatory factors or if pathogenic microorganisms are not promptly cleared, AMs gradually disappear due to cell necrosis (Fan and Fan, 2018). And the recruited monocytes can cause a cascade, waterfall-like cytokine storm inside and outside the lungs, leading to damage to alveolar epithelial cells and pulmonary endothelial cells, causing capillary leakage and diffuse pulmonary interstitial and alveolar edema, ultimately causing patients to develop refractory hypoxemia, and in severe cases, death (Poor and Morales-Nebreda, 2023; Dukhinova et al., 2021; Wang and Wang, 2023).

FIG. 2.

The function of M1. M1 macrophages express a variety of receptors and markers on surface, including MHC-II, TLR4, CD86, CD83, which play crucial roles within the macrophage. They primarily function by activating nuclear transcription factors including NF-κB, IRF, STAT, thereby promoting the production of cytokines including TNF-α, IL-12, IL-27, thus enhancing the inflammatory and antitumor immune responses of M1 macrophages. By Figdraw. TNF, tumor necrosis factor; IL, interleukin; IRF, interferon regulatory factor; STAT, signal transducer and activator of transcription; MHC, major histocompatibility complex.

In the later stages of the inflammatory response, the phenotype of lung macrophages transitions gradually from M1 to M2. M2 express surface receptors and markers such as CD163, CD206, CD209, and IL-4. By activating intranuclear transcription factors such as STAT3, STAT6, and peroxisome proliferator-activated receptor-gamma, they upregulate the expression of IL-10 and Arginase-1, promoting the resolution of inflammation and tissue repair (shown in Fig. 3) (Zhen et al., 2023; Atri et al., 2018; Kang et al., 2021). The phenotype transition of macrophages involves multiple signaling molecules and pathways in the pulmonary microenvironment, making it a complex process. It has been found that pulmonary endothelial cells can promote the transformation of IMs toward M2 by releasing vascular secretory factor R-spondin3. The primary mechanism involves the interaction of R-spondin3 with the anti-inflammatory and reparative receptor leucine-rich repeat-containing G protein-coupled receptor on IMs, triggering the activation of the Wnt/beta-catenin pathway and leading to the upregulation of anti-inflammatory factors such as CD206, CD301, Arginase 1, and IL-10 (Zhang et al., 2024a; Zhou et al., 2020a). IL-10 can inhibit the production of inflammatory cytokines during the acute inflammatory response, thereby alleviating inflammation (Kim et al., 2020). While arginase-1 promotes tissue repair by enhancing the metabolism of arginine (Rath et al., 2014). In this stage, pulmonary macrophages also secrete platelet-derived growth factor (PDGF), VEGFα, and IGF-1 to promote angiogenesis and cell proliferation, collectively helping to alleviate local hypoxia after injury (Du Cheyne et al., 2020). It also induces the production of TGF-β1, stimulating the differentiation of local and recruited tissue fibroblasts into myofibroblasts, promoting wound contraction and the synthesis of extracellular matrix components (Zhang et al., 2021b). In addition, the upregulation of transient receptor potential vanilloid 4 (TRPV4), which is upregulated in the acute inflammatory stage, promotes the phagocytic capacity of macrophages, facilitating the clearance of neutrophils invading the lungs and promoting the resolution of inflammation (Scheraga et al., 2020). On the contrary, the upregulation of apoptosis inhibitor of macrophage inhibits the phagocytic activity of macrophages, impeding the clearance of neutrophils in the late stage of inflammation and the resolution of inflammation (Kimura et al., 2017). During lung injury and development, inflammatory and physical damage factors can activate pulmonary epithelial progenitor cells or stem cells, which then rapidly proliferate and differentiate to replenish damaged cells and promote lung tissue regeneration (Alysandratos et al., 2021). Pulmonary macrophages have the capacity to facilitate lung regeneration, and their interaction with the Wnt pathway is intricately linked. Within the AEC2 population, there exists a subset of Wnt-responsive alveolar epithelial progenitor cells (AEP) that act as the primary facultative progenitors in the distal lung (Raslan and Yoon, 2020). AEPs possess unique transcriptomes, epigenomes, and functional phenotype, with a specific response to the Wnt signaling pathway, and it can rapidly proliferate and produce a large number of AEC2 and AEC1 to promote functional alveolar epithelial regeneration (Zacharias et al., 2018). Macrophages can exacerbate tissue damage on one hand, while playing a role in tissue repair on the other hand. Balancing the role of macrophages correctly is crucial for tissue damage protection (Chen et al., 2021).

FIG. 3.

The function of M2. M2 macrophages also express multiple receptors and markers on surface, including CD163, CD206, CD209, and IL-4, which play crucial regulatory roles within M2 macrophages. They can activate nuclear transcription factors such as STAT3, STAT6, PPARγ, thus promoting the release of cytokines including IL-10, arginase-1, Vascular endothelial growth factor (VEGF), and TGFβ1. M2 macrophages not only exhibit anti-inflammatory activity, promote tissue regeneration and repair, facilitate angiogenesis, and participate in immune regulation but they are also associated with tumor formation and progression. By Figdraw. VEGF, vascular endothelial growth factor; TGF, transforming growth factor; PPARγ, peroxisome proliferator-activated receptor-gamma.

Macrophages in Pulmonary Tuberculosis

Macrophages exhibit a dual role in TB, acting as both favored hiding and replication sites for MTB and displaying antimicrobial capabilities. This dual functionality of macrophages is linked to their activation status, and the extensive apoptosis observed in patients with TB could be considered a component of the host’s defensive tactics as long as these cells remain inactivated (Leemans et al., 2005). The infection with MTB initiates in the distal airways but progressively disseminates to the pulmonary interstitium. The early and extensive MTB infection predominantly occurs in AMs residing in the airways. Subsequently, MTB infection, instead of uninfected AMs, localizes to the pulmonary interstitium prior to phagocytosis by recruited macrophages and neutrophils (Cohen et al., 2018). This propagation process is driven by the MyD88/IL-1 receptor inflammasome signaling (Fremond et al., 2007). In the latent stage of TB infection, the immune system fails to fully recognize and clear MTB, resulting in a state of coexistence known as immune escape. The degree of MTB infection-related harm to the host is associated with its virulence and immune escape from AMs (Naeem et al., 2021). Firstly, MTB directly inhibits the antimicrobial activity of AMs. Macrophage phenotypes can be divided into two main types: M1 and M2. M1 macrophages are primarily tasked with controlling intracellular bacterial infections and impeding tumor advancement. They engage in autonomous defense mechanisms, including phagocytosis, the generation of harmful reactive oxygen and nitrogen molecules, the production of antimicrobial peptides, as well as the maturation of phagosomes and autophagy to break down engulfed pathogens. In contrast, M2 macrophages can create a reparative microenvironment favorable for pathogen survival or tumor expansion. IL-4-activated M2 macrophages promote MTB replication (Chatterjee et al., 2021; Bertolini et al., 2016; Wang et al., 2020a; Ahmad et al., 2022). Studies have shown that the major antigen protein heat shock protein 16.3 (Hsp16.3) on the MTB cell membrane can induce macrophages to produce different cytokines, promoting monocyte and M1 macrophage differentiation into M2 macrophages, thus weakening the antimicrobial activity of AMs (Zhang et al., 2020). The LPS present on the MTB cell wall contributes to its evasion from elimination by AMs. After engulfing MTB, AMs transport and insert LPS into their cell membrane regions rich in glycosylphosphatidylinositol, thereby reducing the production of reactive oxygen and inhibiting their antimicrobial activity and antigen presentation, effectively suppressing specific cellular immunity (Liu et al., 2022a; Mwebaza et al., 2023; Torrelles and Schlesinger, 2010).

In addition, MTB can escape immune recognition by inhibiting the fusion of macrophages with phagosomes and lysosomes and disrupting phagosomes. MTB that is engulfed by AMs can achieve immune escape through direct interactions with macrophages, phagosomes, and lysosomes within macrophages. On one hand, MTB can block the proton pump function on the phagosome membrane to inhibit acidification, preventing phagosome-lysosome fusion and increasing its own survival within phagosomes. On the other hand, MTB secretes acid phosphatase secreted acid phosphatase M to prevent fusion between phagosomes and lysosomes, thereby inhibiting the formation of autophagolysosomes (Krishnan et al., 2023; Carranza and Chavez-Galan, 2019; Zhang et al., 2024b). Highly virulent pathogenic MTB carries the eis gene, which encodes a soluble secreted protein that acts on AMs to reduce the production of TNF-α and increase the secretion of IL-10, thereby inhibiting the activation of AMs and assisting MTB in establishing latency within macrophages (Shin et al., 2010). MTB competes for iron ions with host cells, weakening the activity of AMs and enhancing its own survival (Rodriguez et al., 2022). Moreover, MTB can achieve immune escape by producing specific kinases that can self-phosphorylate or by producing specific proteins that act on macrophage phagosomes. MTB can produce 11 serine/threonine protein kinases, among which protein kinase G (PknG) has the ability to self-phosphorylate by transferring phosphate groups from ATP to its own serine/threonine residues. The self-phosphorylation of PknG can induce MTB to enter a dormant state within AMs, allowing it to persist long-term within these cells (Richard-Greenblatt and Av-Gay, 2017; Prisic and Husson, 2014). MTB can also produce proteins associated with the rupture of phagosomal membranes, causing phagosomal damage. MTB can then transfer from damaged phagosomes into the cytoplasm of macrophages, allowing it to survive and be protected within AMs (Wong, 2017). In addition, MTB can escape by inducing the expression of miRNAs in host cells to regulate the autophagy process. MTB can induce AMs to express multiple miRNAs, including pivotal regulators of the autophagy pathway (such as miRNA-20a and miRNA-20a-5p), leading to several genes related to autophagy in AMs and preventing the completion of the autophagy process (Guo et al., 2016). MTB also inhibits the expression of miRNAs (such as miRNA-26a) that promote autoph suppressing macrophage autophagy and enhancing its own survival within macrophages (Kleinsteuber et al., 2013).

Macrophages are involved in the early response to MTB infection. Furthermore, their involvement is also required during the progression of TB to lung cancer (Bickett and Karam, 2020). Sufficient evidence from epidemiological studies indicates an increased risk of lung cancer with a history of active or previous TB (Fujita et al., 2014). Convincing mechanistic data demonstrate some common features between TB and lung cancer, including chronic inflammation, genomic instability, and replicative immortality (Xiong et al., 2021). Chronic inflammation in the lungs caused by TB may lead to DNA damage in bronchial epithelial cells triggered by activated dendritic cells. Another potential involves horizontal gene transfer, where bacterial integrates into bronchial epithelial cells, inducing tumorigenesis (Molina-Romero et al., 2019). Macrophages infected with MTB associated with the TB-induced carcinogenesis process, contributing to squamous epithelialization and tumor formation through the induction of DNA damage and the production of EREG in their vicinity (Molina-Romero et al., 2019; Nalbandian et al., 2009). In summary, these findings form the basis for the hypothesis that MTB is lung carcinogen (Roy et al., 2021). Due to the involvement of macrophages in the development of human tumors and the dual role of TAMs in tumors, further support is provided for the induction of lung cancer by AMs (Sedighzadeh et al., 2021).

Tumor-Associated Macrophages

TAMs are involved in the occurrence, progression and immune response of tumors, and can be divided into M1 (classically activated macrophages) and M2 (alternatively activated macrophages) (Pan et al., 2020). M1-TAMs express a series of inflammatory factors, chemokines, and effector molecules such as IL-12, IL-27, TNF-α, and MHCII, and possess strong cytotoxic effects (shown in Fig. 2) (Zhuang et al., 2020). In contrast, M2-TAMs express various anti-inflammatory factors including IL-4, IL-10, and TGF-β, which suppress immune function, mediate the secretion of cell factors such as VEGF and matrix metalloproteinases (MMP), and promote tumor metastasis (shown in Fig. 3) (Sedighzadeh et al., 2021; Santoni et al., 2013). Two type TAMs exist in all stages of tumors, with M1 macrophages predominating in the early stages and M2 macrophages predominating in the late stages. As the tumor progresses, there is a gradual polarization of M1 toward M2 (Liu et al., 2021). The polarization of TAMs is reversible and modifiable. Therefore, TAMs have become a hot research topic as relevant targets for treating lung tumors (Wang et al., 2022b).

M1 Macrophages

M1-macrophages can be activated by granulocyte macrophage-colony stimulating factor (GM-CSF), CSF-2, TNF-α, IFN-γ, LPS (Wang et al., 2022a). Cell factors such as LPS or IFN-γ can activate relevant pathways, with the most significant being the upregulation of M1-related gene expression through the intercellular adhesion molecule 1-phosphoinositide 3 (PI3)-kinase (PI3K)-Ser and Thr kinase (Akt)-Notch1 and Janus kinase 1 (JAK1)-STAT1-caspase pathways, leading to the activation of M1 macrophages (Ren et al., 2020; Jiang et al., 2024). Activated M1 macrophages secrete a higher level of TNF-α, IL-12, and reactive oxygen species, participating in the response of the type 1 T helper (Th1) to infection to promote inflammation and resist pathogens, and even induce apoptosis of tumor cells (Pan et al., 2020). M1-macrophages carry specific markers CD83 and CD86, secrete H₂O₂, O₂ ⁻, 1O₂, and other cytotoxic oxygen intermediates, effectively killing tumor cells through oxidative and cytotoxic effects (Kumar et al., 2016; Zhou et al., 2020b). H₂O₂ induces apoptosis of tumor cell by depleting glutathione through MAPK signaling pathway (Park, 2018; Zhu et al., 2023). In addition, M1- TAMs show high expression of TNF-α, which, through its binding with the TNFR on the target cell membrane, carries out its biological functions including cytotoxicity, antiviral activity, and immune regulation. TNF-α binding to the extracellular region of TNF receptor 1 (TNFR1) on the target cell membrane releases TNFR-associated death domain protein (TRADD) inhibitor protein, forming the TNFR1/TRADD complex, leading to the generation and aggregation of a series of related proteins, triggering different downstream signaling pathways, and ultimately causing programmed cell death of tumor cells (Gao et al., 2020). The TNFR1/TRADD complex recruits Fas-associated protein with death domain by binding with its death effector domain and activates caspase-8. This in turn activates caspase-3, causing DNA fragmentation and morphological changes in apoptosis, culminating in the induction of cell apoptosis through a cascade amplification reaction (Wang et al., 2020b; Stennicke et al., 1998).

M1-TAMs can secrete a series of interleukins to participate in immune responses. IL-12 is predominantly produced by monocytes and macrophages, is a heterodimer composed of p35 and p40 (Hayes et al., 1995). It is well known that IL-12 can increase the expression of natural killer (NK) group 2 member D (NKG2D) on cytokine-induced killer (CIK) cells and activate signaling adapter proteins DNAX activation protein DAP-10 and DAP-12 (Huang et al., 2010). CIK cells can form transmembrane channels on tumor cells by releasing perforin and granzyme B, leading to tumor cell lysis, or directly enter the nucleus to kill tumor cells (Yang et al., 2023; Wang et al., 2014). IL-12 upregulates the production of activating receptors (NKp30, NKG2D, NKp44) and downregulates inhibitory receptors (CD158b and CD158a) on NK cells, promoting the secretion of IFN-γ and TGF-β, thereby enhancing the cytotoxicity of NK cells (Carreira-Santos et al., 2023; Sandoval-Borrego et al., 2016). IL-12 enhances NK cell activation by increasing the phosphorylation levels of STAT-4, reversing cisplatin’s inhibitory effects on NK cell secretion of IFN-γ and TNF-α. This suggests that IL-12 can be used for immune reconstitution after chemotherapy or radiotherapy to prevent infections and tumor recurrence, and can serve as an adjuvant therapy for tumors (Xu et al., 2010; Shen et al., 2018). IL-12 can enhance the production of autophagy-related proteins microtubule-associated protein light chain 3 and beclin-1 in cancer cells, promote autophagosome formation, and inhibit cancer cell growth. This may be related to the regulation of the PI3-AKT-mTOR-STAT3 pathway by IL-12 (Liu et al., 2016). IL-12 induces the proliferation of T lymphocytes and NK cells and enhances the activity of both cell types. It regulates the Th0/Th1 ratio, strengthens the biological functions of Th1 cells, and further promotes the production of Inflammation cytokines (Landoni et al., 2024; Germann and Rüde, 1995). IL-12 induces the expression of interferon-γ-inducible protein 10 (IP-10) and MEG proteins by increasing IFN-γ secretion, inhibiting tumor angiogenesis (Kanegane et al., 1998). Meanwhile, IFN-γ inhibits angiogenesis by inducing IP-10 through CXC chemokines and IFN-α, and also inhibiting MMP, contributing to the inhibition of tumor growth and metastasis (Sgadari et al., 1996). IL-27 is a heterodimeric cytokine composed of the EB13 and p28 subunits. IL-27, derived from activated dendritic cells and macrophages, enhances the proliferation and survival of P1CTLs in vitro, induces the generation and activation of effector cytotoxic T cells, thereby enhancing antitumor immunity (Beizavi et al., 2021). IL-27 can activate the STAT1-STAT5 signaling pathways, induce the expression of T-bet to enhance Th1/cytotoxic T cells (Tc1) responses, promote the production of transcription factors including T-bet, Eomes, perforin in CD8+ T cells to enhance their antitumor capabilities (Ding et al., 2022).

M2 Macrophages

M2 macrophages can be activated by IL-4, IL-13, and IL-10. IL-4 and IL-13 promoting M2 macrophage activation via the STAT6 pathway through IL-4 receptor α (Gao et al., 2015; Wang et al., 2022a). In addition, IL-10 can polarize macrophages toward M2 by activating the STAT3 pathway (Sun et al., 2024). Following activation, M2 macrophages secrete various anti-inflammatory factors further accelerate tumor microenvironment (TME) remodeling and promote the survival, growth, and metastasis of tumors through multiple mechanisms (Goswami et al., 2021; Boutilier and Elsawa, 2021). M2-macrophages can promote tumor cell proliferation. Inhibiting the IL-10/JAK1 pathway can suppress the nonsmall cell lung cancer (NSCLC) tumor growth mediated by M2-TAMs and the expression of genes related to CSC and stroma. The expression levels of these signaling molecules are significantly associated with the survival rate of NSCLC patients. Therefore, temporarily removing IL-10 represents an important approach to alleviate the immune suppression associated with myeloid-derived suppressor cells (MDSCs) activity, and is also an effective strategy to enhance the antitumor activity of myeloid-derived dendritic cells and tumor antigen vaccines (Yang et al., 2019). On the other hand, M2-TAMs secrete cytokines including IL-4, CXC chemokine ligand-12, and TGF-β into the TME, inhibiting the activation of cytotoxic T lymphocytes and NK cells, participating in the shaping of conditions conducive to tumor development, directly promoting the growth of tumors, and promoting tumor cell proliferation through the inhibition of the inducible Nitric oxide (iNOS) pathway, reducing NO synthesis and promoting polyamine production (Kashfi et al., 2021). However, more and more studies have shown that the same cytokines can exert different biological effects in different microenvironments, meaning that these cytokines promoting tumor proliferation can also have inhibitory effects. Therefore, the role of these cytokines in the TME has not been fully elucidated and further research is necessary to confirm their effects (Ramesh et al., 2021).

The nutrients required for tumor cell growth are provided by the blood vessels surrounding the tumor. When the tumor reaches a certain size, it experiences inadequate nutrient supply and worsened hypoxia, leading to necrosis. M2-TAMs promote angiogenesis and contribute to tumor growth and development, and they tend to accumulate around poorly vascularized and hypoxic tissues (Dallavalasa et al., 2021). Under hypoxic conditions, the loss of hypoxia-inducible factor 1 leads to TAMs mobilizing and exerting cytotoxic effects, promoting the production of VEGF, Fibroblast growth factor (FGF), Vascular permeability factor (VPF), and Platelet-derived growth factor (PDGF), thereby directly promoting tumor proliferation and angiogenesis (Lu et al., 2023). After hypoxic necrosis, toxins and TNF-α increase in the tumor tissue, activating macrophages and inducing the secretion of high mobility group box 1, which promotes the secretion of highly conserved dimeric protein VEGF. The VEGF family has five members, with VEGF usually referring to VEGF-A in the VEGF family, which primarily functions to promote endothelial cell growth and vessel network formation. M2-macrophages promote stromal vasculogenesis by upregulating the expression of VEGF-A mRNA (Mu et al., 2021). VEGF-C contribute to lymphatic vessel formation through its binding to the specific protein kinase receptor B (TrkB) associated with the tyrosine kinase family. VEGF activates the PI3K/AKT pathway, promoting lymphangiogenesis and repair, and promotes lymph node metastasis of lung cancer (Coso et al., 2012).

The occurrence of cancer is largely due to tumor cells successfully evading T cell-mediated host immune regulation and disease evasion (Tang et al., 2020). TLR4 is highly expressed in M2-TAMs. The TLR4 signaling pathway in the TME can regulate the production of Foxp3 in A549 cells through NF-κB, thereby promoting immune evasion of cancer cells and facilitating tumor progression by activating microenvironment-related immune cells and molecules (Fu et al., 2013; Jia et al., 2012). M2-TAMs secrete cytokines including IL-10, TGF-β to inhibit the activation of normal antigen-presenting-induced T cell activation and the immune defense function of T cells, promoting Treg cell differentiation (Hu et al., 2019; Wang et al., 2017). Treg cells exert negative immune regulation by interfering with the ability of autologous platelet concentrates to activate cells, secreting immunosuppressive factors (Chen et al., 2012b). The interaction between the programmed cell death protein 1 (PD-1) expressed the surface of TAMs and the programmed cell death ligand 1 (PD-L1) expressed on tumor cells can inhibit the phagocytic activity of TAMs, weaken the inherent antitumor immune response, and lead to the occurrence of tumor immune escape (Gianchecchi and Fierabracci, 2018). Furthermore, the surface of TAMs can induce the expression of the B73 molecule, which can inhibit T cell proliferation and the activation of effector T cells. B7 homolog 3 protein (B7-H3, also known as CD276) is not expressed on the surface of normal macrophages but can be induced to express on the surface of TAMs. The TAMs-induced membrane-bound molecule B7-H3 is a new immune escape mechanism (Feng et al., 2021). Recent studies indicates that B7-H3 may regulate the interferon-1 axis in the TME, promoting immune suppression. In addition, B-H3 may be involved in promoting the polarization of TAMs from the M1 to the M2 (Park et al., 2024). TAMs also induce the expression of the B7-H4 molecule on surface of lung cancer cells, which promotes immune escape of tumor cells (Yuan et al., 2020). The later the stage of lung cancer, the higher the proportion of CD68+ TAMs expressing B7-H4 macrophages in the peripheral circulation (Chen et al., 2012a). The dense reticular structure in the tumor stroma acts as a natural barrier during tumor cell infiltration and dissemination. TAMs can secrete MMP, tissue proteinases, and serine proteinases, disrupting the basement membrane of endothelial cells and intercellular connections, modulating the composition of the extracellular matrix, and promoting the diffusion of growth factors in the TME (Winkler et al., 2020). By degrading the endothelial basement membrane of tumor blood vessels and facilitating tumor cell migration, TAMs create a suitable microenvironment for the invasion and progression of NSCLC. Based on these findings, TAMs are becoming a “charismatic target” for tumor therapy (Guan, 2015; Fu et al., 2020).

Conclusion

The lung, due to its unique respiratory function, is highly susceptible to various harmful stimuli from the external environment, leading to tissue damage. Macrophage is the key to the lungs to maintain homeostasis. During lung injury, resident AMs and monocytes recruited to the circulation promote inflammatory response to clear pathogens and harmful substances. However, uncontrolled inflammation can exacerbate tissue damage and hinder lung regeneration. During the later stages of lung injury, macrophages differentiate into an anti-inflammatory phenotype, suppress inflammation, activate AEC2 as progenitor cells of AEC1, undergo self-renewal, mature, and promote tissue regeneration. In pulmonary TB, lung macrophages provide preferred hiding and replication sites for MTB while also exhibiting antimicrobial functions. Moreover, in tumor development, TAMs can produce inflammatory mediators and cytotoxic substances to exert immune and antitumor functions, as well as generate pro-inflammatory and growth factors to suppress immunity and promote tumor growth. The heterogeneity and plasticity of lung macrophages determine their diverse phenotypes and functions in different contexts. We summarize the distinct phenotypes, functions, and related signaling pathways of pulmonary macrophages in homeostasis, inflammatory injury, pulmonary TB, and tumorigenesis.

Footnotes

Author Disclosure Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding Information

Supported by Hunan Provincial Health High-Level Talent Scientific Research Project (grant number: R2023173), Hunan Provincial Natural Science Foundation (Project Number: 2025JJ70052).

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