Chitinase 3-like-1 deficient donor splenocytes accentuated the pathogenesis of acute graft-versus-host diseases through regulating T cell expansion and type I inflammation.
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-γ and TNF-α. 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.
Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, China.
Zengyao
Z
Li
Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, China.
Jian
J
Gu
Department of Radiotherapy, First Affiliated Hospital, Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, China.
Jing
J
Liu
Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, China.
Qin
Q
Zhu
Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, China.
Hao
H
Lu
Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, China.
Yunjie
Y
Lu
Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, China.
Jianhua
J
Rao
Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, China.
Ling
L
Lu
Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, China. Electronic address: wangxh@njmu.edu.cn.
Xuehao
X
Wang
D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D002478:Cells, Cultured; D000071451:Chitinase-3-Like Protein 1 / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006086:Graft vs Host Disease / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology
C509289:Chil1 protein, mouse; D000071451:Chitinase-3-Like Protein 1; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit
CHI3L1; Transplantation; aGVHD