Functional repertoire of interleukin-6 in the central nervous system – a review

1 Introduction—Interleukin-6 (IL-6) signaling

Due to the aging population, neurodegeneration and associated dementia have become major problems in societies worldwide. The development of diverse strategies for the specific treatment of various diseases, such as Alzheimer’s (AD) or Parkinson’s disease (PD), is a major challenge. Interleukin-6 (IL-6), including its receptor system, is a pro-inflammatory cytokine linked to various diseases, including rheumatoid arthritis, inflammatory bowel disease and several types of cancer [reviewed elsewhere: (Calabrese & Rose-John, 2014; Kumari, Dwarakanath, Das, & Bhatt, 2016; Schaper & Rose-John, 2015; Scheller, Garbers, & Rose-John, 2014; Schinnerling, Aguillon, Catalan, & Soto, 2017)].

While IL-6 levels in the body fluids [including serum and cerebrospinal fluid (CSF)] of patients with cognitive deficits, including AD patients, have been reported as altered, reduced or unchanged (Brosseron, Krauthausen, Kummer, & Heneka, 2014; Kim, Lee, & Kim, 2017; Marz et al., 1997; Saleem, Herrmann, Swardfager, Eisen, & Lanctot, 2015; Swardfager et al., 2010), recent accumulating data have correlated IL-6 levels with certain clinicalsymptoms within a wide range of depressive symptomatology and associated IL-6 levels with depression severity (Ali, Hashem, Hassan, Saleh, & El-Baz, 2017; Fan, Luo, Ou, & He, 2017; Jeenger, Sharma, Mathur, & Amandeep, 2017; Zadka, Dziegiel, Kulus, & Olajossy, 2017; Zhang et al., 2017).

However, IL-6 is a multifaceted cytokine that acts as a pro- or anti-inflammatory factor depending on the context and can even be possibly applied as a therapeutic approach to induce regenerative responses in liver, kidney or cancer [reviewed elsewhere: (Galun & Rose-John, 2013; Gao et al., 2016; Kokje et al., 2016; S.Q. Li, Zhu, Han, Lu, & Meng, 2015; Mackiewicz et al., 2015)].

Moreover, IL-6 is also an important player in the central nervous system (CNS) (Erta, Quintana, & Hidalgo, 2012; Gruol, 2015), including its neuroprotective and neuroregenerative effects (Feng, Wang, & Yang, 2015; Y. Gu et al., 2016; Ma, Zhuang, Shen, Peng, & Qiu, 2015; Park, Lin, Li, & Lee, 2015; Xia et al., 2015; G. Yang & Tang, 2017), analgesic and allodynia effects (Ding et al., 2016; Ebbinghaus et al., 2015; Ko et al., 2016; Sainoh et al., 2015), beneficial metabolic anti-obesity effects during health (Lutz, 2016) and metabolic impairment, and neuroinflammation [e.g., in motor neuron degeneration such as amyotrophic lateral sclerosis (ALS)] (Patin et al., 2016). Interestingly, the potential beneficial effects of IL-6 in the brain were previously recognized many years ago by Gadient and Otten (1994–1997) (Gadient & Otten, 1994, 1995, 1997).

The IL-6 receptor family comprises multi-subunit receptors, including the ciliary neurotrophicfactor receptor (CNTFR) and leukemia inhibitory factor receptor (LIFR), associated with a common receptor subunit, the transmembrane protein gp130 (Heinrich et al., 2003; Taga & Kishimoto, 1997). IL-6 mediates its effect via two mechanisms, classical signaling and trans-signaling, where the naturally occurring soluble form of gp80—specific soluble IL-6 receptor (sIL-6R)—acts as an agonist, and the soluble receptor sgp130 acts as antagonist with blocking effects (Figs. 1 and 2) (Garbers, Aparicio-Siegmund, & Rose-John, 2015; Waetzig &Rose-John, 2012; Wolf, Rose-John, & Garbers, 2014). Downstream signaling pathways include the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), mitogen-activated protein kinases (MAPKs), and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) cascades (Schaper & Rose-John, 2015). Accordingly, IL-6 signaling cascades can interfere with growth factor (GF) receptor signaling pathways, such as nerve growth factor (NGF) receptor or epidermal growth factor (EGF) receptor signaling events (Islam, Gong, Rose-John, & Heese, 2009; Ng, Cheung, & Ip, 2006).

OPEN IN VIEWER

Fig.1

Schematic illustration of IL-6-induced classical signaling. This pathway is particularly important for hepatocytes, some leukocytes and microglia (Rothaug, Becker-Pauly, & Rose-John, 2016). Binding of IL-6 to the membrane-bound gp130/IL-6R complex activates JAK. JAK phosphorylates tyrosine residues within the cytoplasmic portion of gp130. These phosphotyrosine motifs (Y-P) are recruitment sites for STAT transcription factors (TFs), the suppressor of cytokine signaling 3 (SOCS3) feedback inhibitor, and adapter protein and phosphatases SHP1 and 2 (protein tyrosine phosphatases PTPN6 and 11 containing two tandem Src homology-2 domains, which function as phosphotyrosine binding domains). SHP1 serves as a negative regulator of STAT3 action.

OPEN IN VIEWER

Fig.2

Schematic illustration of IL-6-induced trans-signaling. This pathway is particularly important for NSCs, astroglia, oligodendroglia and endothelial cells (Rothaug et al., 2016). In this pathway, IL-6 binds to the soluble IL-6 receptor, sIL-6R, and can activate cells via gp130 that usually do not express a membrane-bound IL-6R (gp80). Upon binding of the IL-6/sIL6R complex to the membrane-bound gp130, gp130/JAK activates—similar to the classical pathway—the STAT3 pathway. While SHP1 blocks STAT3 activity, SHP2 links to the MAPK cascade {MAPK1 [mitogen-activated protein kinase 1, also known as extracellular signal-regulated kinases (ERK)]; MAP2K1 [mitogen-activated protein kinase kinase 1, the MAP kinase kinase, which activates ERK, was named “MAPK/ERK kinase” (MEK1)]; RAF1 [a serine/threonine kinase, also known as MAP kinase kinase kinase (MAP3K). Upon activation, RAF1 phosphorylates MEK1 and MEK2, which in turn phosphorylate and thus activate the serine/threonine-specific protein kinases, ERK1 and ERK2]}, which phosphorylates growth factor receptor-bound protein-2 (GRB2)-associated-binding protein 1 (GAB1, not shown). Phosphorylated GAB1 translocates to the plasma membrane where it coordinates ongoing MEK and PI3K (PI3K activates protein kinase B (PKB), also known as AKT) pathway activation. STAT3 can interfere with the MEK and PI3K pathways, which are eventually activated by GFs and the transcription factor cAMP response element-binding protein (CREB) pathways. Src-family kinases (SFK) are recruited independent of receptor phosphorylation and activate the yes-associated protein (YAP, a transcriptional co-activator). While sIL-6R acts as an agonist to mediate IL-6 trans-signaling, soluble gp130 (sgp130) inhibits IL-6 signaling as an antagonist competing for binding to the IL-6/sIL6R complex to prevent its binding to a cell. For clarity, official gene symbols are used instead of gene names in Italics style and protein names in Roman style. Y-P, phosphorylated tyrosine; CH₃, gene methylation. Continuous lines indicate direct protein interactions and known pathways, while dashed lines and ‘?’ indicate indirect protein interactions over several factors involved in pathways that require further investigations to clarify the effect of IL-6-activated signaling pathways during neural differentiations—in particular, interference with classical cytokine pathways (STAT-signaling) by growth factor pathways (MAPK and PI3K-signaling) remains to be elucidated.

IL-6 exerts its neuroprotective effects, inter alia, via cross-talk with brain-derived neurotrophic factor (BDNF) and the adenosine A1 and A2a receptors, resulting in neuroprotection of retinal ganglion cells (Perigolo-Vicente et al., 2014). The potential neuroprotection of IL-6 may result from its inhibitory effects on voltage-gated Na⁺ channel (VGSC) currents (X. Li, Chen, Sheng, Cao, & Wang, 2014; Xia et al., 2015). IL-6 prevents N-methyl-D-aspartate (NMDA)-induced neuronal Ca²⁺ overload viasuppression of inositol trisphosphate (IP3) receptors and through the JAK/STAT3, MAPKs, and PI3K signaling pathways (Fang, Jiang, Han, Peng, & Qiu, 2013; Liu, Fang, Chen, Qiu, & Peng, 2013; Liu, Qiu, Li, Ma, & Peng, 2011; Qiu, Yang, Yuan, Xie, & Liu, 2013; Wang, Qiu, & Peng, 2007). IL-6 reduces NMDA-induced cytosolic Ca²⁺ overload by inhibiting both L-type voltage-gated calcium channel (L-VGCC) activity and intracellular Ca²⁺ release in cultured cerebellar granule neurons (CGNs) (Ma, Li, Huang, Peng, & Qiu, 2012). IL-6 exerts neuroprotection by inhibiting activity of the NMDA receptor subunits NR2B and NR2C (but not NR2A) via mediation of JAK–calcineurin signaling (Ma et al., 2015). IL-6-dependent neuroprotection involves complex interplay among the various cells in the brain, such as microglia, astroglia, and neurons(Shinozaki et al., 2014). With respect to the possible treatment of PD, it is of interest to note that IL-6 protects midbrain dopaminergic (DA) neurons from 1-methyl-4-phenylpyridinium (MPP⁺)-induced neurodegeneration (Spittau, Zhou, Ming, & Krieglstein, 2012). Thus, application of IL-6 or activation of its receptor might provide a suitable strategy for enhancing nerve regeneration (Leibinger et al., 2013).

3 IL-6 and neurogenesis

IL-6 knockout mice show reduced neurogenesis in the hippocampal dentate gyrus and subventricular zone (Bowen, Dempsey, & Vemuganti, 2011). Maternal IL-6 is an essential requirement for the appropriate development of the neural stem cell (NSC) pool in the adult forebrain and olfactory system, with an IL-6-dependent NSC self-renewal pathway (Gallagher et al., 2013). Moreover, disturbances in glycerophospholipid metabolism and tryptophan/kynurenine metabolite secretion are two putative mechanisms by which IL-6 affects the developing nervous system that could eventually contribute to the development of brain disorders such as autism or schizophrenia (Brown et al., 2014).

The JAK/STAT3 pathway supports gliogenesis, while inhibition of STAT3 signaling promotes neurogenesis (Bonni et al., 1997; Cheng, Jin, Zhang, Tian, & Zou, 2011; F. Gu et al., 2005; Oh et al., 2010; Snyder, Huang, & Zhang, 2011). Interestingly, CNTFR/gp130 and LIFR/gp130-mediated signaling support the maintenance of forebrain NSCs, likely by suppressing restriction to a glial progenitor cell fate (Shimazaki, Shingo, & Weiss, 2001). Previously, activated glia cell-derived IL-6 was found to mediate inhibition of neurogenesis and promote gliogenesis—probably as part of a pro-inflammatory process (Nakanishi et al., 2007; Vallieres, Campbell, Gage, & Sawchenko, 2002). However, later reports showed that IL-6 can mediate neurogenesis through its trans-signaling action via STAT3-independent pathways and that CREB is involved (Islam et al., 2009; Oh et al., 2010; Sulistio, Lee, Jung, & Heese, 2017). In the absence of STAT3 activation, cytokines such as IL-6 can still promote neurogenesis as MAPK and other (e.g., PI3K) pathways are still available (Fig. 2) (F. Gu et al., 2005; Islam et al., 2009). While CREB regulates specific phases of adult neurogenesis (Giachino et al., 2005), the specific role of STAT3 in mediating neurogenesis or gliogenesis is stage-dependent; at very early stages, blockade of STAT3 prevents gliogenesis and supports neurogenesis, while at later stages, STAT3 may contribute to neuronal survival and differentiation of NSCs (Cheng et al., 2011) because it not only functions as a transcription factor in the nucleus but also can take part in cytoskeletal modifications in the cytoplasm during neuronal differentiation (D.C. Ng et al., 2006).

IL-6 could be derived from astrocytes or microglial cells (Chucair-Elliott et al., 2014; Oh et al., 2010), although neuronal IL-6 has also been detected in the hippocampus (Gadient & Otten, 1994, 1995) (Fig. 3). Acetylation of STAT3 and methylation (CH₃) of the promoter region of the gene for the astrocyte marker glial fibrillary acidic protein (GFAP) appear to be two mechanisms involved in the control ofneurogliogenesis (Ohbayashi et al., 2007; Taga & Fukuda, 2005). Moreover, potential transactivation of GF receptors, such as the NGF receptor tyrosine kinase receptor TRKA, is another mode of action for the IL-6/sIL-6R system (Chao, 2003; Sorkin, 2005; Sterneck, Kaplan, & Johnson, 1996).

OPEN IN VIEWER

Fig.3

Schematic illustration of IL-6 action in the CNS via classical signaling and trans-signaling activity and its potential application for the treatment of neurodegenerative diseases, such as AD or PD. Neurons, astrocytes, and microglia are all potential sources of IL-6 and sIL-6R expression and release in the CNS under various conditions. Upon injury, IL-6 is secreted and binds to membrane-bound IL-6R expressed in limited cells or to the soluble form of the receptor (sIL-6R) to act as Hyper-IL-6 via trans-signaling. For neuroregenerative purposes, sgp130 could be applied to block some of the deleterious IL-6 trans-signaling effects, while Hyper-IL-6 or sIL-6 could be applied to specifically promote neurotrophic events. Moreover, degenerating neurons or astrocytes send signals to surrounding cells to produce molecules that could activate and attract NSCs to proliferate, migrate, and integrate into existing neural networks to replace dead neurons. This process could be directly supported by the application of Hyper-IL-6 or sIL-6 or by ex vivo application of autologous iPSC-derived NSCs (Pramanik, Sulistio, & Heese, 2017; Sulistio et al., 2017).

Whether an elevated level of IL-6 can significantly improve memory and learning processes via its effects on mechanisms involved in the excitability of neurons at hippocampal synapses remains unclear (Arisi, 2014; Gruol, 2015, 2016; Nelson et al., 2012). Though IL-6 is an important player in the CNS, as an inflammatory cytokine, its effects are not always beneficial and can eventually contribute to neuroimmune diseases such as multiple sclerosis (MS) [for detailed reviews refer to (Cole, Early, & Lyons, 2017; Madsen, 2017; Rothaug et al., 2016)]. However, IL-6 is an important mediator of neurogenesis and aids in long-term functionalrecovery after ischemic stroke (Meng, Zhang, Shi, Zhang, & Yuan, 2015). Interestingly, minocycline, a broad-spectrum tetracycline antibiotic, supports neurogenesis by inhibiting cytokine-mediated gliogenesis and could be applied in combination with IL-6 (Vay et al., 2016).

Furthermore, IL-6 can promote regeneration and functional recovery after nerve injury by reactivating an intrinsic growth program of neurons and enhancing synapse formation (G. Yang & Tang, 2017; P. Yang, Wen, Ou, Cui, & Fan, 2012). The fact that sIL-6 supports agonistic IL-6-mediated neurogenesis makes this combined molecule (known as Hyper-IL-6 or H-IL-6, consisting of IL-6 and sIL-6R combined via a short peptide bond) (Schaper & Rose-John, 2015) an attractive tool for the treatment of neurodegenerative diseases such as PD because the application of NSCs for the treatment of PD has already been widely discussed [including controversial discussion of DA neurogenesis in the adult mammalian substantia nigra (SN) (Farzanehfar, 2016; Morrison, 2016; Napoli & Borlongan, 2017; Radad et al., 2017; Shan et al., 2006; Stoker, Blair, & Barker, 2017)], the neuroprotective potential of IL-6 for DA neurons has been shown (Spittau et al., 2012), and Hyper-IL-6 might also support NSC differentiation into tyrosine-hydroxylase-positive neurons (Erta et al., 2012; Islam et al., 2009). Some of the possible detrimental effects of Hyper-IL-6 trans-signaling in the CNS could be blocked by the application of sgp130 (Campbell et al., 2014). However, sustained IL-6 application should probably be avoided as prolonged exposure to IL-6 may cause clinical symptoms within the wide range of depressive symptomatology (Zadka et al., 2017). Alternatively, autologous NSCs could be generated via induced pluripotent stem cells (iPSCs) and applied in combination with Hyper-IL-6 (Fig. 3) as discussed previously for neurotrophic factors, such as NGF or BDNF (Pramanik, Sulistio, & Heese, 2017; Sulistioet al., 2017).

Conflicts of interest

The author declares that he has no conflicts of interest.