Macrophage-derived VISTA engages with LRIG1 and hinders gut epithelial repair in colitis

Disruption of the intestinal epithelial barrier and incomplete repair are critical for the development of colitis. V-domain immunoglobulin domain suppressor of T-cell activation (VISTA), encoded by Vsir, functions as an immune checkpoint. In the present work, we report that VISTA is predominantly upregulated in macrophages from patients with inflammatory bowel disease (IBD) and in mice with dextran sulfate sodium (DSS)-induced colitis. VISTA deficiency or blockade ameliorates DSS-induced colitis severity. Epithelial damage is notably less severe in Vsir^-/-Rag1^-/- mice than in Vsir^+/+Rag1^-/- mice. Intriguingly, macrophage depletion eliminates disease severity differences between Vsir^-/- and wild-type (WT) mice. Vsir ablation does not alter cytokine profiles or macrophage differentiation but alleviates macrophage-mediated epithelial injury, as Vsir^-/- macrophage transfer induces milder damage than WT macrophage transfer does. Interestingly, Vsir^-/- mice exhibit accelerated mucosal regeneration during acute colitis. Mechanistically, macrophage-derived VISTA interacts with leucine-rich repeats and immunoglobulin-like domain 1 (LRIG1) in intestinal stem cells and suppresses peroxisome proliferator-activated receptor alpha (PPARα), leading to impeded growth of intestinal organoids and increased epithelial damage in mice with DSS-induced colitis. These findings reveal a pathogenic function of macrophage-derived VISTA in epithelial damage during colitis. Targeting the VISTA/LRIG1 axis could promote epithelial repair and serve as a promising therapeutic strategy for patients with IBD.