MAPK signaling mediated intestinal inflammation induced by endoplasmic reticulum stress and NOD2

Endoplasmic reticulum (ER) stress is crucially involved in inflammatory bowel disease (IBD), but the mechanisms remain incompletely understood. This study aimed to elucidate how ER stress promotes inflammation in IBD. ER stress marker Grp78 and NOD2 in colon tissues of Crohn's disease (CD) patients and IBD model mice were detected by immunohistochemical analysis. THP-1 cells were exposed to ER stress and the expression of NOD2 and inflammatory cytokines was detected by PCR. We found that ER stress markers Grp78 and NOD2 were upregulated in intestinal tissues of CD patients and in THP-1 cells exposed to ER stress. ER stress inhibitor reduced Grp78 and NOD2 expression in colitis model mice and alleviated colitis. ER stress inducer cooperated with NOD2 ligand MDP to upregulate TNF-α, IL-8 and IL-1β, and activate MAPK signaling in THP-1 cells. Moreover, inhibitors of MAPK signaling led to the downregulation of IL-1β, IL-8 and TNF-α in THP-1 cells stimulated by ER stress inducer and MDP. In conclusion, ER stress upregulates NOD2 and promotes inflammation in IBD, at least partially due to the activation of MAPK pathway.