Antagonism of Tachykinin receptor 1 promotes Foxp3+ regulatory CD4 T cells and controls gut mucosal inflammation

Abstract Neuroimmune communication of the enteric nervous system (ENS) in gut-associated lymphoid tissues helps to maintain the delicate balance between gut inflammation and tolerance. Substance P (SP) is a neuropeptide neurotransmitter produced by ENS and enteroendocrine cells, lymphocytes, gut macrophages, and brain neurons. SP binds to tachykinin receptors (TACRs, also known as neurokinin receptors). Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) patients are known to have altered TACRs expression and strongly correlate with the pathogenesis of these diseases. How SP-TACR interaction modulates the differentiation and function of inflammatory CD4 T cells (Th1, Th17) and regulatory CD4 T cells (Foxp3+Tregs and Th2 cells) during gut inflammation and autoimmunity is unclear. We showed that among the various subsets of CD4 T cells, splenic Foxp3+Tregs and Th17 cells had the highest expression of TACRs. Agonizing the TACR1 with SP in the dextran sodium sulfate (DSS)-induced colitis in mice exacerbated the disease severity, which was inhibited by treatment with a TACR1-specific antagonist. TACR1 antagonist promoted the differentiation of Foxp3+ Tregs cells, and Tregs induced in the presence of TACR1 antagonist showed an increased expression of LAP1, PD-L1, CD62L, Helios, and CD73 molecules. They suppress the proliferation of effector CD4 T cells and control skin and gut inflammation. We showed that antagonizing the TACR1 signaling promotes Foxp3+ Tregs and controls skin and gut inflammation. Our data suggest that antagonizing the TACR1 provides a clinical advantage in preventing gut inflammation and colitis.