Background:C1q is a soluble pattern recognition protein that regulates multiple leukocyte functions, and deficiency in C1q results in autoimmunity. C1q stimulates enhanced phagocytic function through multiple mechanisms including the rapid enhancement of Fcγ receptor (FcγR) -mediated phagocytosis. The molecular mechanism responsible for this rapid enhancement of phagocytic function is unknown. The purpose of this study was to investigate the molecular pathway required for C1q-dependent enhanced phagocytosis. Results:Leukocyte associated immunoglobulin like receptor-1 (LAIR-1) is a receptor that mediates C1q-dependent activation of leukocytes; however, using LAIR-1 deficient mouse bone marrow derived macrophages (BMDM), we demonstrated that LAIR-1 was not required for C1q-dependent enhanced FcγR-mediated phagocytosis. A phospho-kinase array identified extracellular signal-regulated kinase (ERK) 1/2 as dysregulated following activation with C1q. Validation of the array in BMDM and the human monocyte cell line THP-1 demonstrated a decrease in basal ERK1/2 phosphorylation in C1q-stimulated cells compared to control cells. However, subsequent stimulation with immune complexes stimulated rapid upregulation of phosphorylation. The extracellular matrix protein fibronectin regulates enhanced phagocytic activity in macrophages similar to C1q, and both C1q and fibronectin-dependent enhanced phagocytosis required ERK1/2 since both were blocked by pharmacologic inhibition of ERK1/2. Furthermore, diminished C1q-dependent ERK1/2 phosphorylation was sustained after four-hour treatment with lipopolysaccharide and correlated with a significant reduction in TNFα production. Conclusions:These data demonstrate that C1q and fibronectin utilize a similar ERK1/2-dependent mechanism for enhanced phagocytosis, which should lead to development of novel approaches to modulate C1q-dependent regulation of macrophage activation, inflammation and autoimmunity.Keywords:C1q; Complement; ERK1/2; Fcγ-receptor; Fibronectin; Phagocytosis; TNFα.

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