Adipokine C1q/Tumor necrosis factor- Related Protein 3 (CTRP3) Attenuates Intestinal Inflammation via Sirtuin 1 / NF-κB Signaling.

BACKGROUND & AIMS: The adipokine CTRP3 has anti-inflammatory effects in several non-intestinal disorders. Although serum CTRP3 is reduced in patients with inflammatory bowel disease (IBD), its function in IBD has not been established. Here, we elucidate the function of CTRP3 in intestinal inflammation.

METHODS: CTRP3 knockout (KO) and overexpressing transgenic (Tg) mice, along with their corresponding wild-type (WT) littermates, were treated with dextran sulfate sodium for 6-10 days. Colitis phenotypes and histological data were analyzed. CTRP3-mediated signaling was examined in murine and human intestinal mucosa as well as mouse intestinal organoids derived from CTRP3 KO and Tg mice.

RESULTS: CTRP3 KO mice developed more severe colitis, while CTRP3 Tg mice developed less severe colitis than WT littermates. The deletion of CTRP3 correlated with decreased levels of Sirtuin 1 (SIRT1), a histone deacetylase, and increased levels of phosphorylated / acetylated NF-κB subunit p65 and pro-inflammatory cytokines TNF-α and IL-6. Results from CTRP3 Tg mice were inverse to those from CTRP3 KO mice. The addition of SIRT1 activator resveratrol to KO intestinal organoids and SIRT1 inhibitor Ex-527 to Tg intestinal organoids suggest that SIRT1 is a downstream effector of CTRP3-related inflammatory changes. In IBD patients, a similar CTRP3 / SIRT1 / NF-κB relationship was observed.

CONCLUSIONS: CTRP3 expression levels correlate negatively with intestinal inflammation in acute mouse colitis models and IBD patients. CTRP3 may attenuate intestinal inflammation via SIRT1 / NF-κB signaling. The manipulation of CTRP3 signaling, including through the use of SIRT1 activators, may offer translational potential in the treatment of IBD.