# MG53 protects against intestinal inflammation by inhibiting NLRP3 inflammasome activation

## TL;DR

MG53 protects against intestinal inflammation by inhibiting the NLRP3 inflammasome, which could lead to new treatments for inflammatory bowel disease.

## Contribution

MG53 is identified as a novel physiological regulator of NLRP3 inflammasome activation in colitis.

## Key findings

- MG53 knockout mice showed more severe colitis symptoms compared to wild-type mice.
- Recombinant MG53 reduced NLRP3 inflammasome activation and inflammation in mouse models.
- MG53 interacts with NLRP3 to inhibit ASC speck formation and NLRP3 oligomerization.

## Abstract

Inflammatory bowel disease (IBD) involves dysregulated immune responses and chronic intestinal inflammation. The nod-like receptor pyrin domain–containing 3 (NLRP3) inflammasome plays a critical role in IBD pathogenesis, but regulatory mechanisms remain not fully understood. Mitsugumin 53 (MG53, also known as TRIM72), originally identified as a critical membrane repair protein, has emerged as a novel regulator of inflammatory processes. To investigate the protective role of MG53 in colitis and elucidate its mechanisms in regulating NLRP3 inflammasome activation in IBD.

We used dextran sodium sulfate (DSS)-induced colitis models comparing MG53 knockout (MG53
−/−) and wild-type (WT) mice, assessing disease severity, MG53 tissue uptake, and therapeutic effects of recombinant human MG53 (rhMG53). In vitro studies examined rhMG53’s effects on NLRP3 inflammasome activation, caspase-1 cleavage, interleukin-1β (IL-1β) secretion, and MG53-NLRP3 interactions.

MG53
−/− mice showed more severe colitis with increased weight loss, higher disease activity scores, shortened colons, and greater inflammation. DSS treatment induced the accumulation of circulating MG53 in inflamed colonic tissue. rhMG53 administration ameliorated colitis severity in MG53
−/− mice and dose-dependently suppressed NLRP3 inflammasome activation in vitro. MG53 interacted with NLRP3 and reduced apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and NLRP3 oligomerization without affecting upstream signaling or NLRP3 stability.

MG53 is a physiological regulator of NLRP3 inflammasome activation that protects against colitis, suggesting therapeutic potential for IBD.