Cytokine-Induced Alterations of α7 Nicotinic Receptor in Colonic CD4 T Cells Mediate Dichotomous Response to Nicotine in Murine Models of Th1/Th17- versus Th2-Mediated Colitis

Abstract

Ulcerative colitis (UC) and Crohn’s disease (CD) are two forms of chronic inflammatory bowel disease. CD4 T cells play a central role in the pathogenesis of both diseases. Smoking affects both UC and CD but with opposite effects, ameliorating UC and worsening CD. We hypothesized that the severity of gut inflammation could be modulated through T-cell nicotinic acetylcholine receptors (nAChRs) and that the exact clinical outcome would depend on the repertoire of nAChRs on CD4 T cells mediating each form of colitis. We measured clinical and immunologic outcomes of treating BALB/c mice with oxazolone- and TNBS-induced colitides by nicotine. Nicotine attenuated oxazolone colitis, which was associated with increased percentage of colonic Tregs and a reduction of Th17 cells. TCR stimulation of naïve CD4+CD62L+ T cells in the presence of nicotine upregulated expression of Foxp3. In marked contrast, nicotine worsened TNBS colitis, and this was associated with increased Th17 cells among colonic CD4 T cells. Nicotine upregulated IL-10 and inhibited IL-17 production, which could be abolished by exogenous IL-12 that also abolished the nicotine-dependent upregulation of Tregs. The dichotomous action of nicotine resulted from the up- and downregulation of anti-inflammatory α7 nAChR on colonic CD4 T cells induced by cytokines characteristic of the inflammatory milieu in oxazolone (IL-4), and TNBS (IL-12) colitis, respectively. These findings help explain the dichotomous effect of smoking in patients with UC and CD, and underscore the potential for nicotinergic drugs in regulating colonic inflammation.

The vagal innervation of the gut and immune homeostasis

“…76 Although there is no clear explanation for this difference, a recent report using two models of murine colitis mimicking Th1 or Th2 type of inflammation has shown that the divergent effect of nicotine may be explained by the upregulation of the α7nAChR by a Th2 inflammatory response (ulcerative colitis) but not by a typical Th1/Th17 inflammatory response. 77 Assuming that the therapeutic response of nicotine (or smoking) is mediated by α7nAChR, these findings may explain the differential effect of smoking in Crohn's versus ulcerative colitis patients. To what extent this difference in α7nAChR expression also applies to IBD patients remains to be investigated.…”

The cholinergic anti-inflammatory pathway ameliorates acute viral myocarditis in mice by regulating CD4+ T cell differentiation

“…Nizri et al also demonstrated that nicotine treatment inhibited the response of Th1 and Th17 cells and attenuated neuroinflammation in autoimmunity encephalomyelitis [17]. Nicotine treatment could ameliorate inflammatory bowel disease severity through increasing the proportion of Treg cells and decreasing the proportion of Th17 cells [11]. In this research, we proposed that the CAP could regulate the differentiation of CD4 + T cells in viral myocarditis.…”

“…Our previous studies have indicated that the CAP significantly decreases the level of Th17 cell-related IL-17A and IL-6 as well as Th1 cell-associated TNF-α [6–10]. Galitovskiy et al also found that α7-nicotinic acetylcholine receptor (α7-nAChR) agonist, nicotine, increased the ratio of Treg cells and reduced the ratio of Th17 cells, improving the prognosis of ulcerative colitis [11]. These results suggest that CAP may regulate the differentiation of CD4 + T cells in VMC mice.…”

CCR6-CCL20 Axis in IBD: What have we learnt in the past 20 years?

“…Nicotine was shown to abrogate oxazolone -colitis via the up regulation of colonic Treg cells and decreased TH17 although TNBS-colitis was exacerbated with an elevation of TH17 cells in the colon. They suggested that nicotinic receptors expressed bispecific action by stimulating IL-10 release and attenuating IL-17 secretion or stimulating IL-17 production which confirmed that smoking could induce opposing effects in CD and UC affected individuals [29].…”