LAUSR

Abstract Acute graft‐versus‐host disease (aGVHD) is a major complication following transplantation, limiting the success of this therapy. Chitinase 3‐like‐1 (CHI3L1), a member of the glycosyl hydrolase 18 family, plays a critical role in bacterial infections, allergic disease and a variety of malignancies. Here, we investigated whether CHI3L1 could affect the pathogenesis of aGVHD in a mouse allo‐HCT model. In this study, we show that CHI3L1 deficiency in donor T cells increased the severity of aGVHD through enhancing systemic and local inflammation. In addition, we found that aGVHD induced by CHI3L1‐knockout (CHI3L1‐KO) donors resulted in massive expansion of donor CD3+ T cells, release of Th1‐related cytokines and chemokines, and significant inhibition of CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) without changing the suppressive ability of donor Tregs remarkably. Expression of PERK1/2 and PAkt increased both in the skin and intestine from CHI3L1‐KO splenocytes‐treated aGVHD mice. Moreover, at mRNA and protein levels, we defined several molecules that may account for the enhanced ability of CHI3L1‐KO splenocytes to migrate into target organs and produce Th1‐related cytokines and chemokines, such as CXCL9, CXCL11, IFN‐&ggr; and TNF‐&agr;. Therefore, these results imply that CHI3L1 levels in donor cells may be related to the risk of aGVHD and targeting CHI3L1 may be a promising clinical strategy to control aGVHD. HighlightsWe present a novel molecular CHI3L1 which plays an important role in regulating the pathophysiology of aGVHD.Several molecules may account for the enhanced pathogenesis of aGVHD caused by CHI3L1 deficiency in donors, such as CXCL9, CXCL11, IFN‐&ggr; and TNF‐&agr;.CHI3L1 absence promotes the expansion of T cells.CHI3L1 absence significantly inhibits Tregs.ERK1/2 and Akt pathway participates in the function of CHI3L1 in regulating aGVHD.