The role of the intracellular ‘C5 system’ in sterile inflammation
Aberrant crystallization of organic material in the host can cause an inflammatory response that is associated with the pathogenesis of various severe diseases, hence the immune system sensors recognize pathological crystals as danger. Crystalline cholesterol (CC) is a key mediator of atherogenesis. Phagocytosis of CC causes lysosomal damage, NLRP3 inflammasome assembly, and subsequent release of mature IL-1β. We have recently shown that intracellular complement activation (the complosome) provides an essential signal for NLRP3 inflammasome activation within human T cells which in turn is needed for protective Th1 immunity. We are currently investigating if such complosome-inflammasome crosstalk is also required for monocyte-driven sterile inflammation. Initial data are supporting this hypothesis:
Similar to T cells, human monocytes harbor an intracellular complement C5 system. During CC sensing, TLR-mediated induction of intracellular C5 activation into C5a and C5b drives the engagement of the intracellular C5a receptor 1 (C5aR1) which is critical to the induction of reactive oxygen species (ROS), NLRP3 inflammasome activation and IL-1β secretion. Importantly, inhibition of C5 expression in monocytes or pharmacological targeting of the intracellular (but not extracellular) C5aR1 diminished CC (and MSU crystal) induced IL-1β secretion to the same extent as NLRP3 inhibition. In line with this, monocytes from patients lacking serum C5 but producing intracellular C5/C5a, mounted normal strong IL-1β response upon CC sensing. We are currently assessing if Ldlr–/– mice that lack the C5aR1 specifically in monocytes are less susceptible to cholesterol/high fat diet induced atherosclerosis.
Our ongoing work suggests that a controlled cross-talk between an intracellularly-active, autocrine, complosome and the NLRP3 inflammasome is a requirement for DAMPs sensing and the induction of sterile inflammation in humans – and elevates complement potentially as prime therapeutic target in cardiovascular disease.