期刊
JCI INSIGHT
卷 3, 期 24, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.121697
关键词
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资金
- NIH [R01 CA118116, R01 CA169116, R01 AI118305, R21 CA192202, R01 CA173687, R01 CA088932, R01 DE016572, P01 CA203628, C06 RR15455, P30 CA138313]
- SmartState Endowment in Lipidomics and Drug Discovery
- Australian National Health and Medical Research Council [1117017, 1145372]
- National Health and Medical Research Council of Australia [1145372] Funding Source: NHMRC
=Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT). DCs play critical roles in GVHD induction. Modulating autophagy represents a promising therapeutic strategy for the treatment of immunological diseases. Complement receptors C3aR/C5aR expressed on DCs regulate immune responses by translating extracellular signals into intracellular activity. In the current study, we found that C3aR/C5aR deficiency enhanced ceramide-dependent lethal mitophagy (CDLM) in DCs. Cotransfer of host-type C3aR(-/-) /C5aR(-/-) DCs in the recipients significantly improved GVHD outcome after allogeneic HCT, primarily through enhancing CDLM in DCs. C3aR/C5aR deficiency in the host hematopoietic compartment significantly reduced GVHD severity via impairing Th1 differentiation and donor T cell glycolytic activity while enhancing Treg generation. Prophylactic treatment with C3aR/C5aR antagonists effectively alleviated GVHD while maintaining the graft-versus-leukemia (GVL) effect. Altogether, we demonstrate that inhibiting C3aR/C5aR induces lethal mitophagy in DCs, which represents a potential therapeutic approach to control GVHD while preserving the GVL effect.
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