A New IRAK-M-Mediated Mechanism Implicated in the Anti-Inflammatory Effect of Nicotine via α7 Nicotinic Receptors in Human Macrophages

Abstract

Nicotine stimulation of α7 nicotinic acetylcholine receptor (α7 nAChR) powerfully inhibits pro-inflammatory cytokine production in lipopolysaccharide (LPS)-stimulated macrophages and in experimental models of endotoxemia. A signaling pathway downstream from the α7 nAChRs, which involves the collaboration of JAK2/STAT3 and NF-κB to interfere with signaling by Toll-like receptors (TLRs), has been implicated in this anti-inflammatory effect of nicotine. Here, we identifiy an alternative mechanism involving interleukin-1 receptor-associated kinase M (IRAK-M), a negative regulator of innate TLR-mediated immune responses. Our data show that nicotine up-regulates IRAK-M expression at the mRNA and protein level in human macrophages, and that this effect is secondary to α7 nAChR activation. By using selective inhibitors of different signaling molecules downstream from the receptor, we provide evidence that activation of STAT3, via either JAK2 and/or PI3K, through a single (JAK2/PI3K/STAT3) or two convergent cascades (JAK2/STAT3 and PI3K/STAT3), is necessary for nicotine-induced IRAK-M expression. Moreover, down-regulation of this expression by small interfering RNAs specific to the IRAK-M gene significantly reverses the anti-inflammatory effect of nicotine on LPS-induced TNF-α production. Interestingly, macrophages pre-exposed to nicotine exhibit higher IRAK-M levels and reduced TNF-α response to an additional LPS challenge, a behavior reminiscent of the ‘endotoxin tolerant’ phenotype identified in monocytes either pre-exposed to LPS or from immunocompromised septic patients. Since nicotine is a major component of tobacco smoke and increased IRAK-M expression has been considered one of the molecular determinants for the induction of the tolerant phenotype, our findings showing IRAK-M overexpression could partially explain the known influence of smoking on the onset and progression of inflammatory and infectious diseases.

Cross-talk between α7 nAChR-mediated cholinergic pathway and acylation stimulating protein signaling in 3T3-L1 adipocytes: role of NFκB and STAT3

“…It seems that only very few factors were capable of activation of STAT3 in adipocytes Chatterjee et al 2009;Horiguchi et al 2008;Murray 2006;Maldifassi et al 2014;Balhoff and Stephens 1998;Valentino et al 2013;Serrano-Marco et al 2011). Although the constitutive expression of total STAT3 protein is not changed with ASP or GTS-21 alone or together, our results confirm that depletion of STAT3 protein exacerbates the inflammatory response and support the notion that normal existence of STAT3 is a prerequisite for transition to its active phosphorylated form.…”

“…Nicotine exerts anti-inflammatory effects through reducing tyrosine 705 phosphorylation of STAT3 in IL-6+IL-6SR-treated endothelial cells without modification on the constitutive serine 727 phosphorylation of STAT3 (Chatterjee et al 2009). Conversely, in LPS-treated macrophage, nicotine exerts the same effects via increasing tyrosine phosphorylation (de Jonge and Ulloa 2007;Horiguchi et al 2008;Murray 2006;Maldifassi et al 2014) and suppressing serine 727 phosphorylation of STAT3 . These data collectively implied that the controversial effect of both tyrosine and serine phosphorylation of STAT3 may depend on cell type and stimuli.…”

“…We further found that ASP is able to influence STAT3 serine phorsphorylation. Typically, both tyrosine and serine phosphorylation are commonly required simultaneously for stimuli, to carefully and differentially regulate transcription Horiguchi et al 2008;Murray 2006;Maldifassi et al 2014). Yet observation shows that there are exceptions to STAT3 tyrosine phosphorylation without serine phosphorylation (Chung et al 1997).…”

“…STAT3 pathway may converge with NFB pathway to relay inflammatory signaling (Lee et al 2009). In addition, STAT3 could inactivate the activity of NFB (de Jonge and Ulloa 2007; Park et al 2008;Chatterjee et al 2009;Horiguchi et al 2008;Murray 2006;Maldifassi et al 2014). Therefore, we used stattic, a selective inhibitor of STAT3 phosphorylation, to confirm whether STAT3 was involved in ASP-induced NFB activation and MCP-1 secretion.…”

T-cell receptors modify neuronal function in the central nervous system

“…It is possible that infiltration of blood cells such as T lymphocytes in the damaged areas after stroke, brain or spinal cord injuries may activate either MHC-TCR complexes in neurons or microglia and contribute to decreased neurotransmission and therefore, dysfunction of neural circuits. Interestingly, both microglia and macrophages contain a7 nAChRs and therefore may play some role in the neuroinflammatory response after stroke or trauma [50,51]. Indeed, there is a cholinergic anti-inflammatory pathway mediated by the vagus nerve acting on a7 nAChRs on macrophages [52].…”