Th175 - Intracellular Membrane Attack Complexes Function as Non-Cytolytic Alarmins in Transplant Rejection

Matthew Fan – Yale University School of Medicine; Quan Jiang – Yale University School of Medicine; Mahsa Nouri Barkestani – Yale University School of Medicine; Guiyu Song – Yale University School of Medicine; Qianxun Wang – Yale University School of Medicine; Shaoxun Wang – Yale University School of Medicine

Abstract Text: Complement membrane attack complexes (MACs) are well known mediators of cell death, but these structures are frequently detected within inflamed tissues following solid organ transplantation in the absence of widespread necrosis. As a basis for these observations, we describe an alternate immune function for MACs as non-cytolytic, intracellular alarmins. MAC+ amyloid deposits form in cohorts with antibody-mediated rejection, and MAC+ protein aggregates inducibly form in vivo and in human tissues. Following their assembly, surface-bound MACs become internalized into Rab5+ vesicles whose intraluminal milieu causes C9, a MAC-associated protein, to form insoluble aggregates. C9 aggregates subsequently stimulate aggrephagy to induce NF-B-dependent inflammatory genes. Our lab recently discovered a novel Rab5 effector protein called ZFYVE21. We newly generated endothelial cell-specific ZFYVE21 knockout mice and found that these mice show attenuated C9 aggrephagy and reduced alloimmune tissue injury. Our findings describe a novel immune function for MACs as non-cytolytic, intracellular alarmins.