Figure 4.

Role of complement in the activation of inflammasomes in innate immune cells during sepsis.

Notes: The complement (C3b)-opsonized bacteria phagocytosed via MAC cause the binding of MAC to the macrophage membrane, which leads to the initiation of bystander damage via the upregulation and activation of NLRP3 inflammasome. The activation of NLRP3 causes activation of CASP1, which leads to the maturation and release of proinflammatory cytokines, IL-1β and IL-18. On the other hand, the sublethal form of the MAC called sublethal MAC also induces the activation of NLRP3 inflammasome and the release of IL-1β and IL-18 via increasing the intracellular Ca²⁺ which enters into the mitochondrial matrix. The increase of Ca²⁺ in the mitochondrial matrix leads to increased mtROS generation and alters the mitochondrial membrane potential, causing mitochondrial damage and the release of mitochondrial DNA into the cytosol. All these factors activate NLRP3 inflammasome. Additionally, binding of C3a to its cognate receptor C3aR also activates NLRP3 inflammasome via activating the ERK1/ERK2 pathway which causes the efflux of ATP that activates NLRP3 inflammasome via binding to P2X₇. The ATP that gets converted into adenosine via the enzymatic action of CD39 and CD73 also activates NLRP3 inflammasome by binding to A₂AR.

Abbreviations: A₂AR, A₂A receptor; ATP, adenosine triphosphate; MAC, membrane attack complex; mtDNA, mitochondrial DNA; mtROS, mitochondrial reactive oxygen species.