Loss of WNT5 Proteins Reprograms Neutrophils in the Spleen to Provide Protection for DSS-Induced Colitis

Abstract

AbstractWNT5A and WNT5B are two close homologs, both of which are implicated in the pathogenesis of inflammatory bowel diseases. However, the roles these two proteins play in the disease remain largely uncharacterized. Here, we report that double knockout ofWnt5aandWnt5b(Wnt5DKO) protects mice from Dextran Sodium Sulfate (DSS)-induced colitis in mice, accompanied with greater splenomegaly, stronger expansion of peripheral myeloid cells, and less colonic CD8+T cell granzyme B expression than those of the control mice. Depletion of neutrophils or splenectomy abrogates the phenotypic differences betweenWnt5DKO and control mice largely by exacerbating colitis phenotypes and increasing colonic CD8+T cell GZMB expression in theWnt5DKO mice. In addition, neutrophils from theWnt5DKO colitic mice exert stronger suppression of CD8+T cells than those from the control mice in culture. Single-cell RNA sequencing and proteomic analyses indicate that neutrophils from DSS-treatedWnt5DKO mice are of hyper-immunosuppressive and hypo-inflammatory characteristics and are distinct from those of DSS-treated control mice as well as myeloid-derived suppressor cells in tumor-bearing mice. Thus, our study reveals that the lack of WNT5 reprograms neutrophils in spleens to limit colonic injury during DSS-induced colitis.