The C3a receptor, caspase-1, and release of IL-1β

Inflammasomes: Pandora’s box for sepsis

“…232 The binding of C3a to C3aR on macrophages induces ERK-1/2 phosphorylation which further promotes the efflux of ATP from the macrophages (Figure 4). 232,233 Thereafter, the binding of extracellular ATP to a P2X 7 receptor or the conversion of ATP into adenosine via CD39 and CD73 and its binding to adenosine A 2 receptors both cause activation of NLRP3 inflammasome and CASP1 during sepsis 191,200,205. The C1q component of CS acts as a negative regulator of inflammasome activation during the uptake of apoptotic cells and directs macrophage polarization via decreasing the cleavage of proCASP1 to CASP1 required for the release of IL-1β 234.…”

Complement as a vital nexus of the pathobiological connectome for acute respiratory distress syndrome: An emerging therapeutic target

“…Activated macrophages are highly phagocytic, and also release effector molecules such as cytokines and chemokines (136,137), which can rapidly recruit neutrophils into the injury site (138). Activated complement products (C3a, C5a, and C5b-9) also function as "alarmins," initiating secretion of both IL-1 and IL-18 at NLRP3-, ASC-, and caspase-1-dependent manner in macrophages via two signal pathways: (1) the priming signal, triggered by the signal axis of C3a/C5a-C3aR/C5aR-MAPKs-NF-kB/AP-1, leading to the transcriptional upregulation of canonical and non-canonical NLRP3 inflammasome components (139)(140)(141); and (2) the activation signal, which is elucidated through the cascades of C3a-C3aR-ERK1/2-ATP-P2X7, C5a-C5aR-mitochondria-ROS, and C5b-9-ATP influx/K+ efflux (140)(141)(142)(143)(144). Genetic deletion of C6 in mice resulted in a deficiency of NLRP3 inflammasomes in macrophages and neutrophils that resulted in less lung damage and improved survival after sepsis (145).…”

Coupling Factors: How Many Candidates Can There Be?

“…For the latter, among the many outstanding questions are: What other osteoblast lineage genes are affected by actions through the C3aR in osteoblasts and at what stage of osteoblast differentiation does C3aR optimally act? Because the macrophage is such a prominent target of C3a action, is C3aR mRNA so evident in calvarial osteoblasts because of the macrophage content of mouse calvarial cultures? Macrophage‐mediated actions of C3a need to be considered in both the in vitro and in vivo experiments of the present work, in view of the known activation through Ca3R in monocytes and macrophages of mediators such as IL‐1β through participation of Toll‐like receptor and ATP‐mediated P2X purinoreceptor (P2 × 7) signals in monocytes and macrophages . Further, the fact that C3a circulates in such substantial amounts (approximately 50 ng/mL in human serum) might call into question a role for C3a only at selected sites in the skeleton as they undergo remodeling.…”

“…(7) Macrophage-mediated actions of C3a need to be considered in both the in vitro and in vivo experiments of the present work, in view of the known activation through Ca3R in monocytes and macrophages of mediators such as IL-1b through participation of Toll-like receptor and ATP-mediated P2X purinoreceptor (P2 Â 7) signals in monocytes and macrophages. (8,9) Further, the fact that C3a circulates in such substantial amounts (approximately 50 ng/mL in human serum) (10) might call into question a role for C3a only at selected sites in the skeleton as they undergo remodeling.…”