Abstract / Summary
Abstract CD103+dendritic cells (DCs) are immunoregulatory cells that curb inflammation and preserve gut‑liver immune homeostasis. However, the gut‑liver profile of CD103⁺ DCs and their upstream regulatory mechanisms in metabolic dysfunction‑associated steatohepatitis (MASH) remain undefined. This study aimed to investigate how STAT3 in colonic epithelial cells (CECs) modulates the differentiation of gut‑liver CD103⁺ DCs during MASH pathogenesis. Wild-type, CEC-specific STAT3 knockout (CKO) mice and littermate control mice were fed either an AMLN diet or methionine‑ and choline‑deficient (MCD) diet to establish experimental MASH. We observed a gut-liver dysregulation of CD103+DCs in mice with MASH, with an elevated proportion in the colon yet reduced abundance in the liver. Upregulation of the Aldh1a1/retinoic acid (RA) axis within CECs underpinned this gut‑liver imbalance of CD103+DCs in MASH mice. In vitro assays demonstrated that STAT3 directly bound to the promoter of Aldh1a1 and negatively regulated its transcription in CECs. CEC‑specific STAT3 deletion aggravated RA metabolic disorder, further disrupted CD103⁺ DC gut‑liver homeostasis, and accelerated MASH progression. RA supplementation or CD103⁺ DC transfer reversed the detrimental effects of CEC STAT3 knockout on MASH. STAT3 in CECs suppresses MASH progression by targeting Aldh1a1 promoter, limiting over-production of RA in CECs and thereby maintaining the gut-liver homeostasis of CD103+DCs. Our findings highlight a crucial role of epithelial STAT3 and support its therapeutic potential for MASH.