Complement Protein C1q Directs Macrophage Polarization and Limits Inflammasome Activity during the Uptake of Apoptotic Cells

Abstract

Deficiency in C1q, the recognition component of the classical complement cascade and a pattern recognition receptor involved in apoptotic cell clearance, leads to lupus-like auto-immune diseases characterized by auto-antibodies to self proteins and aberrant innate immune cell activation likely due to impaired clearance of apoptotic cells. Here, we developed an autologous system using primary human lymphocytes and monocyte-derived macrophages (HMDMs) to characterize the effect of C1q on macrophage gene expression profiles during the uptake of apoptotic cells. C1q bound to autologous apoptotic lymphocytes modulated expression of genes associated with JAK/STAT signaling, chemotaxis, immunoregulation and NLRP3 inflammasome activation in LPS-stimulated HMDMs. Specifically, C1q sequentially induced type I interferons (IFNs), IL-27 and IL-10 in LPS-stimulated HMDMs and IL-27 in HMDMs when incubated with AL conditioned media. Co-incubation with C1q tails prevented the induction of type I IFNs and IL-27 in a dose dependent manner and neutralization of type I IFNs partially prevented IL-27 induction by C1q. Finally, C1q decreased procaspase-1 cleavage and caspase-1 dependent cleavage of IL-1β suggesting potent inhibitory effect of C1q on inflammasome activation. These results identify specific molecular pathways induced by C1q to suppress macrophage inflammation providing potential therapeutic targets to control macrophage polarization, and thus inflammation and autoimmunity.

Anti-C1q Autoantibodies from Systemic Lupus Erythematosus Patients Induce a Proinflammatory Phenotype in Macrophages

“…However, in accordance with previous reports (18,21), imC1q significantly downregulated LPS-induced secretion of proinflammatory cytokines, such as IL-1b, IL-6, and TNF-a, compared with HSA alone (IL-1b/IL-6: p = 0.031, TNF-a: p = 0.0435) ( Fig. 2A-C, upper panels).…”

“…Additionally, studies from different research groups demonstrated that C1q enhances the uptake of apoptotic cell material, as well as skews the cytokine profile released by phagocytic cells toward a less inflammatory response during phagocytosis (17)(18)(19)(20). During the uptake of early and late apoptotic cells, C1q exerted a potent inhibitory effect on macrophage-mediated inflammation (21). These data suggest that C1q is crucial in limiting inflammation during the uptake of apoptotic cells.…”

“…For example, regarding cytokine secretion and cytokine mRNA levels, C1q induces a decreased inflammatory response in phagocytes in combination with a proinflammatory stimulus, such as LPS (18,21). Therefore, we next assessed whether anti-C1q bound to imC1q changed the LPS-induced cytokine profile secreted by HMDMs compared with imC1q or HSA alone.…”

C1q-induced LRP1B and GPR6 Proteins Expressed Early in Alzheimer Disease Mouse Models, Are Essential for the C1q-mediated Protection against Amyloid-β Neurotoxicity

“…C1q is known, however, to be a multifunctional macromolecule with some inherent functions independent of its association with C1r and C1s such as enhancing clearance of apoptotic cells by phagocytic cells (including microglia) and modulating cytokine production to limit inflammation (2)(3)(4). In addition, synthesis of the complement protein C1q has been found upregulated in the brain in response to a variety of neuronal injuries, including models of AD (1,(5)(6)(7).…”

Complement activation and regulation in preeclamptic placenta

“…Our results support the theory, that C1q has an important role in the maintenance of immune tolerance by clearing apoptotic and self-antigens. C1q has an important ability to recognize altered or exposed structures of self thereby leading to their efficient clearance by phagocytes without lysis and inflammation (22). Direct binding of C1q may occur to various structures, such as to phospholipids or vimentin exposed by vascular endothelia during tissue damage (23).…”