1. Complement C3a and C5a receptors promote GVHD by suppressing mitophagy in recipient dendritic cells.
- Author
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Nguyen H, Kuril S, Bastian D, Kim J, Zhang M, Vaena SG, Dany M, Dai M, Heinrichs JL, Daenthanasanmak A, Iamsawat S, Schutt S, Fu J, Wu Y, Fairlie DP, Atkinson C, Ogretmen B, Tomlinson S, and Yu XZ
- Subjects
- Animals, Apoptosis, Autophagy, Cell Differentiation, Dendritic Cells metabolism, Disease Models, Animal, Female, Hematopoietic Stem Cell Transplantation, Humans, Lymphocyte Activation, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Receptor, Anaphylatoxin C5a genetics, Receptor, Anaphylatoxin C5a metabolism, T-Lymphocytes, T-Lymphocytes, Regulatory immunology, Th1 Cells, Dendritic Cells immunology, Graft vs Host Disease immunology, Mitophagy, Receptor, Anaphylatoxin C5a immunology
- Abstract
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.
- Published
- 2018
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