Complement C3a and C5a receptors promote GVHD by suppressing mitophagy in recipient dendritic cells
Hung Nguyen, Sandeepkumar Kuril, David Bastian, Jisun Kim, Mengmeng Zhang, Silvia G. Vaena, Mohammed Dany, Min Dai, Jessica Lauren Heinrichs, Anusara Daenthanasanmak, Supinya Iamsawat, Steven Schutt, Jianing Fu, Yongxia Wu, David P. Fairlie, Carl Atkinson, Besim Ogretmen, Stephen Tomlinson, Xue-Zhong Yu
Hung Nguyen, Sandeepkumar Kuril, David Bastian, Jisun Kim, Mengmeng Zhang, Silvia G. Vaena, Mohammed Dany, Min Dai, Jessica Lauren Heinrichs, Anusara Daenthanasanmak, Supinya Iamsawat, Steven Schutt, Jianing Fu, Yongxia Wu, David P. Fairlie, Carl Atkinson, Besim Ogretmen, Stephen Tomlinson, Xue-Zhong Yu
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Research Article Stem cells Transplantation

Complement C3a and C5a receptors promote GVHD by suppressing mitophagy in recipient dendritic cells

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.

Authors

Hung Nguyen, Sandeepkumar Kuril, David Bastian, Jisun Kim, Mengmeng Zhang, Silvia G. Vaena, Mohammed Dany, Min Dai, Jessica Lauren Heinrichs, Anusara Daenthanasanmak, Supinya Iamsawat, Steven Schutt, Jianing Fu, Yongxia Wu, David P. Fairlie, Carl Atkinson, Besim Ogretmen, Stephen Tomlinson, Xue-Zhong Yu

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Figure 4

C3aR/C5aR deficiency of recipients ameliorates GVHD via increasing lethal mitophagy in recipient DCs.

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C3aR/C5aR deficiency of recipients ameliorates GVHD via increasing letha...
(A and B) Lethally irradiated WT or C3aR–/–/C5aR–/– BALB/c recipients (n = 12–15) were transplanted with TCD-BM (5 × 106/mouse) with or without T cells (1 × 106/mouse) from B6 mice and monitored for survival (A) and clinical scores (B). (C and D) B6 recipients were transplanted with BM (5 × 106/mouse) plus purified T cells (1 × 106/mouse) from FVB donors (n = 7–10). Survival (C) and clinical score (D) are shown. (E and F). Spleens and thymi were isolated from transplanted recipients in A 80 days after HCT. (E) The number of CD4+CD8+ cells in the thymi and of donor CD4, CD8, and B220 cells in the spleens (n = 3). (F) The levels of cytokine in recipient sera 14 days after HCT (n = 2–3). (G and H) Lethally chimeras B6 recipients ([WT→WT], [WT→C3aR–/–/C5aR–/–], [C3aR–/–/C5aR–/–→WT], and [C3aR–/–/C5aR–/–→C3aR–/–/C5aR–/–]) were transplanted with BM alone (5 × 106/mouse) or BM plus purified T cells (2 × 106/mouse) from FVB donors. Survival (G) and clinical score (H) are shown (n = 10). (I and J) Lethally irradiated B6 recipients (n = 10–12/group) were transplanted with BM (3 × 106/mouse) plus purified T cells (1 × 106/mouse) from FVB donors. Recipients also received 2 × 106 WT or C3aR–/–/C5aR–/–B6 BM-DCs, previously cultured overnight with hydroxyl chloroquine (HQ) (5 mg/ml), on the transplanted day. Survival (I) and clinical score (J) are shown. The log-rank (Mantel-Cox) test (A, C, G, and I), nonparametric Mann-Whitney U test (B, D, H, and J), and unpaired t test (E and F) were used to compare between groups. Data are represented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.