Inflammatory bowel disease (IBD) is a chronic relapsing gastrointestinal disorder

while the treatment effect is not satisfactory. Immune responsive gene 1 (

IRG1

) is a highly expressed gene in macrophage in response to inflammatory response and catalyzes the production of itaconate. Studies have reported that IRG1/itaconate has a significant antioxidant effect. This study aimed to investigate the effect and mechanism of IRG1/itaconate on dextran sulfate sodium (DSS)-induced colitis

in vivo

and

in vitro

.

In vivo

experiments

we found IRG1/itaconate exerted protective effects against acute colitis by increasing mice weight

the length of colon

reducing disease activity index and colonic inflammation. Meanwhile

IRG1 deletion aggravated the macrophages/CD4

+

/CD8

+

T-cell accumulation

and increased the release of interleukin (IL)-1β

tumor necrosis factor-α (TNF-α)

IL-6

the activation of nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) signaling pathway

and gasdermin D (GSDMD) mediated pyroptosis. Four-octyl itaconate (4-OI)

a derivative of itaconate

attenuated these changes

therefore relieved DSS-induced colitis.

In vitro

experiment

we found 4-OI inhibited the reactive oxygen species production

thereby inhibiting the activation of MAPK/NF-κB signaling pathway in RAW264.7 and murine bone-marrow-derived macrophages. Simultaneously

we found 4-OI inhibited caspase1/GSDMD-mediated pyroptosis to reduce the release of cytokines. Finally

we found anti-TNF-α agent reduced the severity of DSS-induced colitis and inhibited gasdermin E (GSDME)-mediated pyroptosis

in vivo

. Meanwhile

our study revealed that 4-OI inhibited caspase3/GSDME-mediated pyroptosis induced by TNF-α

in vitro

. Taken together

IRG1/itaconate exerted a protective role in DSS-induced colitis by inhibiting inflammatory response and GSDMD/GSDME-mediated pyroptosis

which could be a promising candidate for IBD therapy.