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Mitochondrial C5aR1 activity in macrophages controls IL-1β production underlying sterile inflammation

ABSTRACT: While serum-circulating complement destroys invading pathogens, intracellularly active complement, termed the ‘complosome’, functions as a vital orchestrator of cell-metabolic events underlying T cell effector responses. Whether intracellular complement is also non-redundant for the activity of myeloid immune cells is currently unknown. Here, we show that monocytes and macrophages constitutively express complement component (C) 5 and can generate autocrine C5a via formation of an intracellular C5 convertase. Further, cholesterol crystal-sensing by macrophages induces C5aR1 signaling on mitochondrial membranes, which shifts ATP production via reverse electron chain flux towards reactive oxygen species (ROS) production and anaerobic glycolysis to favor IL-1β production. Consequently, atherosclerosis-prone mice lacking macrophage-specific C5ar1 had ameliorated cardiovascular disease on a high-cholesterol diet. Conversely, inflammatory gene signatures and IL-1β produced by cells in unstable atherosclerotic plaques of patients were normalized by a specific cell-permeable C5aR1 antagonist. Deficiency of the macrophage cell autonomous C5 system also protected mice from crystal nephropathy mediated by folic acid. These data demonstrate unexpected intracellular formation of a C5 convertase and identify C5aR1 as a direct modulator of mitochondrial function and inflammatory output from myeloid cells. Together, these findings suggest that the complosome is a novel contributor to the biologic processes underlying sterile inflammation and indicate that targeting this system could be beneficial in macrophage-dependent diseases, such as atherosclerosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE162389 | GEO | 2021/12/30

REPOSITORIES: GEO

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Project description:The complement system is part of the innate immune system that works to clear pathogens and cellular debris. In the central nervous system (CNS) complement activation can promote synaptic pruning clearance of neuronal blebs recruitment of phagocytes and protection from pathogens. However in a neuropathologic environment complement activation may contribute to inflammatory pathways neuronal dysfunction and in the Alzheimer’s disease (AD) brain cognitive decline. If complement activation proceeds to the cleavage of C5 and thus generation of C5a engagement of C5a with the receptor C5aR1 can instigate a feed-forward loop of inflammation injury and neuronal death thus making this molecule a potential target for modulation in AD therapeutics. The Arctic (Arc) AD mouse model known to rapidly accumulate fibrillar amyloid plaques was crossed to a model that lacks the receptor for C5a (ArcC5aR1KO) or to a transgenic mouse that generates C5a under the GFAP promoter (ArcC5a+). ArcticC5a+ mice showed accelerated loss of spatial memory compared to Arc mice. While eliminating C5aR1 did not alter amyloid plaque accumulation in this AD model C5aR1KO delayed or prevented the expression of important AD-associated genes in the hippocampus indicating a separation between those genes induced by amyloid plaques and those influenced by C5a-C5aR1 signaling. C5ar1 deletion also reduced/delayed the expression of select pan-reactive and A1 reactive astrocyte genes. ArcC5aR1KO showed delayed expression of genes enriched for biological processes that are significant in the AD context such as regulation of inflammatory signaling microglial cell activation astrocyte migration and lysosome pathway. Interestingly overexpression of C5a also delayed the increase of some AD- complement and astrocyte-associated genes perhaps mediated by C5aR2 and emphasizing the importance of selectively suppressing C5aR1. Immunohistochemical investigation further confirmed that modulation of C5a-C5aR1 either delayed or reduced some reactive microglial markers in the Arc hippocampus including CD11b and CD11c. These results suggest that C5a-C5aR1 signaling in the context of AD largely exerts its effects by suppressing those microglial activation pathways that accelerate disease enhancing pathways. Given the highly focused modulation of a common driver of neurotoxicity pharmacological inhibition of this C5aR1 signaling pathway is a promising therapeutic strategy to treat AD.

Project description:Atherosclerosis is the preliminary cause of coronary artery disease, one of the diseases that ac-count for the largest number of fatal mortalities. Physical activity is an effective strategy to restrain atherosclerosis from deterioration. Evidence indicated that the changes of proteomic profile is highly associated with the atherosclerosis development, but the mechanism behind the exercise for atherosclerosis amelioration has not yet been investigated from the proteomics perspective. Hence, the proteomic profiles could further elucidate the systematic effects of exercise interven-tion on ApoE knockout atherosclerotic model and high fat diet intervention. In current study, Apoeem1Narl/Narl mice were randomly allocated into a normal diet (ND), western diet (WD) and WD with 12 weeks exercise intervention (WD EX) groups. The plasm proteome between WD and WD EX demonstrate the significant difference, and ten major pathways, including cardiovascular disease (CVD)–hematological disease, cellular compromise–inflammatory response, protein synthesis, connective tissue disorders, cellular movement–immune cell tracking, inflammatory response, etc., were generated by the IPA analysis. The fourteen proteins (PROS, PROZ, C2, F5, C5, SERPINA 10, FGB, FGG, CFB, F12, CRP, CFHR1, HABP2, and PPIA) critically involved in CVD–hematological disease pathway showed significant difference among groups. The PROS, F5, C5, FGG, and CFB levels associated with thrombosis and atherosclerosis induced by WD were significantly decreased by exercise intervention in WD EX. Furthermore, the F5 and FGG were well-demonstrated the important roles for thrombosis of atherosclerotic pathogenesis but the complement factor C5 in the development of atherosclerosis is not fully understood. In current study, the exercise could significantly alleviate the significantly elevated C5 and inflammation induced by WD group in accordance to amelioration of atherosclerosis. Therefore, exercise could mitigate chemotaxis through the modulation of the C5 level and innate immunity, thereby alle-viating the pathogenesis of atherosclerosis in western-diet induced obese mice.

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Mitochondrial C5aR1 activity in macrophages controls IL-1β production underlying sterile inflammation

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