Neurological and immunological signals constitute an extensive regulatory network in our body that maintains physiology and homeostasis. The cholinergic system plays a significant role in neuroimmune communication, transmitting information regarding the peripheral immune status to the central nervous system (CNS) and vice versa. The cholinergic system includes the neurotransmitter\ molecule, acetylcholine (ACh), cholinergic receptors (AChRs), choline acetyltransferase (ChAT) enzyme, and acetylcholinesterase (AChE) enzyme. These molecules are involved in regulating immune response and playing a crucial role in maintaining homeostasis. Most innate and adaptive immune cells respond to neuronal inputs by releasing or expressing these molecules on their surfaces. Dysregulation of this neuroimmune communication may lead to several inflammatory and autoimmune diseases. Several agonists, antagonists, and inhibitors have been developed to target the cholinergic system to control inflammation in different tissues. This review discusses how various molecules of the neuronal and non-neuronal cholinergic system (NNCS) interact with the immune cells. What are the agonists and antagonists that alter the cholinergic system, and how are these molecules modulate inflammation and immunity. Understanding the various functions of pharmacological molecules could help in designing better strategies to control inflammation and autoimmunity.

The chemokine receptor CCR9 and its only known ligand CCL25 play an important role in gut inflammation and autoimmune colitis. The function of CCR9‐CCL25 in the migration of immune cells is well characterized. However, its role in the immune cell differentiation is mostly not known. Using dextran sodium sulfate (DSS)‐induced gut inflammation model, we showed that CCR9+ dendritic cells (DCs) specifically CD11b−CD103+ DCs were significantly increased in the gut‐associated lymphoid tissues (GALT) compared to control mice. These CCR9+ DCs express lower MHC II and CD86 molecules and had regulatory surface markers (FasL and latency‐associated peptide, LAP) in the GALT. In the presence of CCL25, CCR9+ DCs promoted in vitro differentiation of Foxp3+ regulatory CD4+ T cells (Tregs). CCL25‐induced differentiation of Tregs was due to intrinsic signaling in the DCs but not through CD4+ T cells, which was driven by the production of thymic stromal lymphopoietin (TSLP) and not IL‐10. Furthermore, adoptive transfer of CCR9+ DCs in C57BL/6 mice promoted Tregs but reduced the Th17 cells in the GALT, and also suppressed the OVA‐specific gut‐allergic response. Our results suggest CCR9+ DCs have a regulatory function and may provide a new cellular therapeutic strategy to control gut inflammation and allergic immune reaction.

Chemokine receptor CCR9 is known to play an important role in the migration of immune cells to the gut. Intestinal epithelial cells under gut inflammation or in inflammatory bowel disease (IBD) produce several folds higher CCL25, the only known ligand for CCR9, and drive the recruitment of CCR9+ immune cells. Due to its gut tropism activity, CCR9 and CCL25 are suggested as a potential therapeutic target. Still, many of the clinical trials targeting CCR9/CCL25 did not give a positive outcome; instead, they increase the severity of the disease. The non-chemotactic function of CCR9 in the gut inflammation and immunity is not known. Using dextran sodium sulfate (DSS)-induced gut inflammation model in C57BL/6 mice, we showed that CCR9+ DCs, specifically CD11b−CD103+ DCs recruited in high frequency to the gut and gut-associated lymphoid tissues (GALT) in DSS treated mice as compared to control group. These CCR9+ DCs showed lower MHC II and CD86 molecules and had higher regulatory surface markers (FasL and Latency-associated peptide, LAP) in the GALT. Further, we demonstrate that thymic stromal lymphopoietin (TSLP) produced by CCR9+ DCs but not IL-10 or TGF-β, promotes the differentiation of Foxp3+ Treg. Furthermore, adoptive transfer of CCR9+ DCs in C57BL/6 mice promoted Tregs but reduced the Th17 cells in the GALT, and also suppressed the ovalbumin-specific gut allergic immune response. Together, these results suggest that CCR9+ DCs have a regulatory function and can be explored as an adoptive cellular therapy to control the gut inflammation and allergic immune response.