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 1

Complement C3aR/C5aR signaling suppresses mitophagy that is required for survival and activation of host DCs after TBI.

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Complement C3aR/C5aR signaling suppresses mitophagy that is required for...
(A–E) WT and C3aR–/–/C5aR–/– mice were irradiated at 700 cGy. (A) Quantification of splenic DCs (MHCII+CD11c+) 24 hours after TBI. (B) Summary of the frequencies of live recipient DCs (Live/dead– [L/D–]) and necrotic DCs (L/D+Annexin V+) (n = 4). (C) Summary graphs for the mean of fluorescence (MFI) and representative histogram of annexin V and Fas. (D) Cyto-ID expression of splenic DCs (n = 3–4). (E) The protein expression of LC3B-I/LC3B-II and p62 of splenic DCs determined by Western blot. (F and G) Irradiated BM-DCs were matured with 20 ng/ml LPS and were dual stained with MitoTracker red (MTR) and LysoTracker green (LTG) (original magnification, ×25) (F) or with ceramide antibody and mitochondrial marker Tom20 (original magnification, ×63) (G). White arrows indicate colocalization (n = 3). Unpaired 2-tailed t test was used to compare between groups. Data were representative of 2 independent experiments and are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.