C1q as an autocrine and paracrine regulator of cellular functions

Abstract

Most of the complement proteins in circulation are, by and large, synthesized in the liver. However data accumulated over the past several decades provide incontrovertible evidence that some if not most of the individual complement proteins are also synthesized extrahepatically by activated as well as non-activated cells. The question that is finally being addressed by various investigators is: are the locally synthesized proteins solely responsible for the myriad of biological functions in situ without the contribution of systemic complement? The answer is probably “yes”. Among the proteins that are synthesized locally, C1q takes center stage for several reasons. First, it is synthesized predominantly by potent antigen presenting cells such as monocytes, macrophages and dendritic cells (DCs), which by itself is a clue that it plays an important role in antigen presentation and/or DC maturation. Second, it is transiently anchored on the cell surface via a transmembrane domain located in its A chain before it is cleaved off and released into the pericellular milieu. The membrane-associated C1q in turn, is able to sense danger patterns via its versatile antigen-capturing globular head domains. More importantly, locally synthesized C1q has been shown to induce a plethora of biological functions through the induction of immunomodulatory molecules by an autocrine- or paracrine-mediated signaling in a manner that mimics those of TNFα. These include recognition of pathogen- and danger-associated molecular patterns, phagocytosis, angiogenesis, apoptosis and induction of cytokines or chemokines that are important in modulating the inflammatory response. The functional convergence between C1q and TNFα in turn is attributed to their shared genetic ancestry. In this paper, we will infer to the aforementioned “local-synthesis-for-local function” paradigm using as an example, the role played by locally synthesized C1q in autoimmunity in general and in systemic lupus erythematosus in particular.

The immune cell landscape in kidneys of lupus nephritis patients

“…Cluster CM1 expressed upregulated levels of phagocytic receptors CD36 (SCARB3), SCARB2, CD68, CD163, NR1H3 (LXR), and GPNMB and cluster CM4 expressed VSIG4, MSR1, CD163, MERTK, STAB1 and CD209. Cells in CM1 and especially CM4 had upregulated expression of C1Q, which not only acts as an opsonin for phagocytosis but also promotes apoptotic cell clearance by enhancing the expression of MERTK (in the presence of other molecules, such as HMGB1) and its soluble ligand GAS6 10,11 . Clusters CM1 and CM4 also expressed the highest levels of the sialic acid binding immunoglobulin lectin CD169 (SIGLEC1), an endocytic receptor that has been detected on infiltrating macrophages in a variety of human renal inflammatory diseases and that is associated with a phagocytic and reparative phenotype 12 .…”

The role of complement components C1q, MBL and C1 inhibitor in pathogenesis of endometriosis

“…These include the recognition of pathogen- and danger-associated molecular patterns, phagocytosis, angiogenesis, apoptosis and induction of cytokines or chemokines that are important in modulating the inflammatory response. The functional convergence between C1q and TNF-α in turn is attributed to their shared genetic ancestry [ 18 ]. Moreover, studies have shown that C1q can play an important role in other diseases, including autoimmunological diseases [ 19 ].…”

The complex functioning of the complement system in xenotransplantation

“…Complement factors help induce inflammation against microbial invasion, and cross‐react with toll‐like receptors (TLRs), inflammasomes, and the acute‐phase protein (or C‐reactive protein, C‐RP). C1q partially shares the same role as TNF‐α …”

“…C1q partially shares the same role as TNF-α. 27 Innate immune cells (neutrophils macrophages, dendritic cells…”