Intracellular complement activation—An alarm raising mechanism?

Abstract

It has become increasingly apparent that the complement system, being an ancient defense mechanism, is not operative only in the extracellular milieu but also intracellularly. In addition to the known synthetic machinery in the liver and by macrophages, many other cell types, including lymphocytes, adipocytes and epithelial cells produce selected complement components. Activation of e.g. C3 and C5 inside cells may have multiple effects ranging from direct antimicrobial defense to cell differentiation and possible influence on metabolism. Intracellular activation of C3 and C5 in T cells is involved in the maintenance of immunological tolerance and promotes differentiation of T helper cells into Th1-type cells that activate cell-mediated immune responses. Adipocytes are unique in producing many complement sensor proteins (like C1q) and Factor D (adipsin), the key enzyme in promoting alternative pathway amplification. The effects of complement activation products are mediated by intracellular and cell membrane receptors, like C3aR, C5aR1, C5aR2 and the complement regulator MCP/CD46, often jointly with other receptors like the T cell receptor, Toll-like receptors and those of the inflammasomes. These recent observations link complement activation to cellular metabolic processes, intracellular defense reactions and to diverse adaptive immune responses. The complement components may thus be viewed as intracellular alarm molecules involved in the cellular danger response.

Selective and marked decrease of complement receptor C5aR2 in human thoracic aortic aneurysms: a dysregulation with potential inflammatory effects

“…However, the immune cell infiltration did not differ from samples obtained from non-aneurysmatic atherosclerotic thoracic aortas, underscoring the need for appropriate controls when studying non-syndromic TAA. Interestingly, however, C5aR2 in media of TAA patients were colocalised with T cells and macrophages showing intracellular localisation in both cell types, as also have been reported by others in others in various tissues 35. Verghese et al have recently reported that C5aR2 augment the activation of regulatory T cells promoting cardiac allograft survival in an experimental mouse model, supporting an anti-inflammatory role of C5aR2 also within the T cell population 36.…”

Anti-Cancer Effects of Panax ginseng Berry Polysaccharides via Activation of Immune-Related Cells

“…The complement system was originally revealed as a heatsensitive element in fresh serum that "complemented" the effects of particular antibody during the lysis of red blood cells and bacteria (West et al, 2018). It is an important effector of the humoral immunity (Noris and Remuzzi, 2013) and represents a highly integrative system with a number of functions, including removal of injured cells and debris, host defense, regenerative processes, modulation of metabolism, and regulation of adaptive immunity (Reichhardt and Meri, 2018). Ginsenan, acidic polysaccharides To deplete NK cells in vivo, rabbit anti-asialo GM1 serum was injected into mice 1 and 3 days before inoculation of B16BL6 melanoma cells.…”

Pathological significance of C3aR signaling in the tumor cells of clear cell renal cell carcinoma: a clinical observation

“…Also, C3aR signaling was found to be involved in the induction of in ammatory cytokines [25], proliferation of mesangial [11] and carcinoma cells [12] and EMT of tubular epithelial cells [10]. Recently, C3aR signaling was believed to be an important factor in maintaining cellular homeostasis [26][27].…”