C1q-mediated chemotaxis by human neutrophils: involvement of gClqR and G-protein signalling mechanisms

Abstract

C1q, the first component of the classical pathway of the complement system, interacts with various cell types and triggers a variety of cell-specific cellular responses, such as oxidative burst, chemotaxis, phagocytosis, etc. Different biological responses are attributed to the interaction of C1q with more than one putative cell-surface C1q receptor/C1q-binding protein. Previously, it has been shown that C1q-mediated oxidative burst by neutrophils is not linked to G-protein-coupled fMet-Leu-Phe-mediated response. In the present study, we have investigated neutrophil migration brought about by C1q and tried to identify the signal-transduction pathways involved in the chemotactic response. We found that C1q stimulated neutrophil migration in a dose-dependent manner, primarily by enhancing chemotaxis (directed movement) rather than chemokinesis (random movement). This C1q-induced chemotaxis could be abolished by an inhibitor of G-proteins (pertussis toxin) and PtdIns(3,4,5)P3 kinase (wortmannin and LY294002). The collagen tail of C1q appeared to mediate chemotaxis. gC1qR, a C1q-binding protein, has recently been reported to participate in C1q-mediated chemotaxis of murine mast cells and human eosinophils. We observed that gC1qR enhanced binding of free C1q to adherent neutrophils and promoted C1q-mediated chemotaxis of neutrophils by nearly seven-fold. Our results suggests C1q-mediated chemotaxis involves gC1qR as well as G-protein-coupled signal-transduction mechanisms operating downstream to neutrophil chemotaxis.

The Classical and Regulatory Functions of C1q in Immunity and Autoimmunity

“…Soluble C1q stimulates mast cell, neutrophil and eosinophil chemotaxis (102)(103)(104) (Figure 2). In view that C1q is predominantly found in the plasma, the significance of C1q in chemotaxis is unclear.…”

Essential Role of Phosphoinositide 3-Kinase δ in Neutrophil Directional Movement

“…Both wortmannin and LY294002, two widely used inhibitors of PI3Ks, block PIP3 generation and chemotaxis (19,22). However, these inhibitors do not distinguish among the four class I PI3Ks and also inhibit protein kinases.…”

Soluble gC1qR Is an Autocrine Signal That Induces B1R Expression on Endothelial Cells

“…Although a detectable amount of B1R exists on the cell surface, B1R is induced by IL-1b produced by monocytes recruited to the inflammatory site. Third, sgC1qR is capable of inducing B1R expression and, thus, enhancing BKmediated vascular permeability, and it is also able to recruit C1q, a powerful chemoattractant (35,36), which like activated HK, is able to generate proinflammatory cytokines, such as TNF-a, IL-1b, and IL-6, and the chemokines IL-8 and MCP-1 (37,38). Thus, at sites of inflammation or diseases states, such as angioedema, in which vascular permeability plays a central role, gC1qR can serve as an important catalyst by orchestrating various proinflammatory cascades.…”