MicroRNA-124 mediates the cholinergic anti-inflammatory action through inhibiting the production of pro-inflammatory cytokines

Abstract

The vagus nerve can control inflammatory response through a 'cholinergic anti-inflammatory pathway', which is mediated by the α7-nicotinic acetylcholine receptor (α7nAChR) on macrophages. However, the intracellular mechanisms that link α7nAChR activation and pro-inflammatory cytokine production remain not well understood. In this study, we found that miR-124 is upregulated by cholinergic agonists in LPS-exposed cells and mice. Utilizing miR-124 mimic and siRNA knockdown, we demonstrated that miR-124 is a critical mediator for the cholinergic anti-inflammatory action. Furthermore, our data indicated that miR-124 modulates LPS-induced cytokine production by targeting signal transducer and activator of transcription 3 (STAT3) to decrease IL-6 production and TNF-α converting enzyme (TACE) to reduce TNF-α release. These results also indicate that miR-124 is a potential therapeutic target for the treatment of inflammatory diseases.

The cholinergic anti-inflammatory pathway meets microRNA

“…Nicotine and choline inhibit LPSinduced STAT3 Tyr705 phosphorylation, similar to that reported for JAK2 inhibitor or stattic, a typical inhibitor of STAT3 tyrosine phosphorylation [9,10]. These findings suggest that the cholinergic anti-inflammatory pathway is independent of the STAT3 tyrosine phosphorylation, but it requires STAT3 protein expression, suggesting that unphosphorylated STAT3 (U-STAT3) mediates the anti-inflammatory potential of α7nAChR.…”

“…Likewise, nicotine inhibits the NF-κB pathway via STAT3 but independently of the traditional STAT3 transcriptional modulation [8,9]. Despite controversy on the STAT3 phosphorylation, all the studies indicate that STAT3 protein expression is critical for the cholinergic inhibition of the NF-κB pathway [8][9][10]. The role of STAT3 in the cholinergic anti-inflammatory pathway was first shown in postoperative paralytic ileus, a common postsurgical pathology characterized by the inflammation of the intestinal muscularis.…”

“…In a recent paper in Cell Research, Sun et al [10] show that nicotine can inhibit both STAT3 tyrosine phosphorylation and protein expression by inducing the microRNA-124 (miR-124) via α7nAChR. miR-124 agomir inhibits STAT3 protein levels and LPS-induced IL6 and TNF production.…”

MicroRNA-124 loaded nanoparticles enhance brain repair in Parkinson's disease

“…For example, injection of 6-OHDA in mice led to a reduction in SVZ proliferation [56,57], yet the levels of neuroblasts in SVZ and RMS were not affected and a higher survival of neurons in the OB was detected [57]. We also observed a reduction in SVZ proliferation caused by 6-OHDA that as neuroprotection [20,21] or reduction of neuroinflammation [58][59][60]. Taken together, our results suggest that miR-124 NPs are an attractive future therapeutic approach to potentiate the endogenous recovery of the injured brain, namely in PD.…”

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

“…Interestingly, recent data indicate that vagal tone also regulates innate immune system responses through the activation of CD4+ T cells that have the capacity to produce and release acetylcholine (RosasBallina et al, 2011). Relevant to innate immune regulation and inflammation, acetylcholine is capable of binding to the α7 nicotinic acetylcholine receptor on macrophages and other cell types leading to inhibition of NF-κB, a process that involves microRNA-124 (Sun et al, 2013). In addition, α7 nicotinic receptor signaling can inhibit inflammasome activation in macrophages by preventing the release of mitochondrial DNA, a DAMP and thus a NLRP3 ligand (Lu et al, 2014).…”