Figure 8.

Graphical Abstract (illustrated using Biorender). At homeostasis, ENS is the major producer of NPY, and NPY is regulated via auto feedback regulation via Y1 and Y2 receptors in the ENS. NPY from ENS binds to Y1 receptors on enteric immune cells and induces TNF production. During inflammation, in addition to ENS, enteric immune cells also produce NPY, which binds to immune cells and induce more TNF via Y1. Hence, with intracolonic NPY1R inhibition using BIBP, we observed reduction of TNF release, and other cytokines like IL-12, IL-6, and IL-5 (DSS and adoptive T-cell transfer colitis), and TNF and IFN-ϒ (UC biopsies). However, Y2 receptor on ENS and T cells mediate feedback regulation of NPY production, and Y2 inhibition by BIIE caused reduction of IL-5 (adoptive T-cell transfer colitis) and IFN-ϒ (UC biopsies).