C1q Differentially Modulates Phagocytosis and Cytokine Responses during Ingestion of Apoptotic Cells by Human Monocytes, Macrophages, and Dendritic Cells

Abstract

C1q, the first component of the classical complement pathway, is also a pattern recognition receptor involved in the recognition and clearance of apoptotic cells. C1q deficiency in humans leads to development of lupus-like autoimmune disease, and it has been speculated that impaired clearance of apoptotic cells may contribute to disease development. Since phagocytes initiate specific and appropriate immune responses as a result of initial ligand-receptor interactions, regulation of gene expression by C1q may also contribute to the sculpting of an immune response to the ingested “self-Ags.” In this study, the role of C1q in apoptotic cell clearance and subsequent modulation of cytokine release by phagocytes was assessed including donor matched human monocytes, monocyte-derived macrophages (HMDMs), and dendritic cells (DCs). First, C1q binding is much greater to late compared with early apoptotic cells. Second, C1q binding to apoptotic cells significantly enhanced the levels of ingestion by monocytes but had no effect on HMDM and DC uptake. Third, in the presence of serum, C1q bound to apoptotic cells, activated the complement pathway, leading to C3b deposition, and enhancement of uptake of apoptotic cells by monocytes, HMDMs, and DCs. Finally, although C1q, either immobilized on a plate or bound to apoptotic cells, modulates the LPS-induced cytokine levels released by human monocytes, HMDMs, and DCs toward a more limited immune response, both the degree and direction of modulation differed significantly depending on the differentiation state of the phagocyte, providing further evidence of the integration of these cell- and environment-specific signals in determining appropriate immune responses.

Annexin A2 and A5 Serve as New Ligands for C1q on Apoptotic Cells

“…To support this, evidence has been presented supporting the role of C1q in development of tolerance (46), clearance of immune complexes (47), and cytokine regulation (48). It differentially modulates the phagocytosis and cytokine responses during ingestion of apoptotic cells by human monocytes, macrophages, and dendritic cells as well as of apoptotic neurons by microglia (49,50). Clearly, C1q has many functions crucial for homeostasis and prevention of SLE.…”

An Alternative Role of C1q in Bacterial Infections: FacilitatingStreptococcus pneumoniaeAdherence and Invasion of Host Cells

“…The C-terminal globular head region of C1q functions as a patternrecognition molecule and mediates binding to various molecules exposed on the surface of apoptotic cells such as DNA and calreticulin (43,44) and thus acts as a bridging molecule between apoptotic cells and APCs such as macrophages and dendritic cells (45)(46)(47). Although, a number of C1q ligands have been characterized on apoptotic cells, the list is relatively short in the case of bacterial pathogens.…”

Identification of a Cytochrome P4502E1/Bid/C1q-dependent Axis Mediating Inflammation in Adipose Tissue after Chronic Ethanol Feeding to Mice

“…Our recent work has identified a critical link between ethanol-induced apoptosis in liver and complement activation via C1q (27); similar links between neuronal apoptosis, C1q, and inflammation are found in some murine models of Alzheimer disease (38). Interestingly, C1q can also play a protective role in models of Alzheimer disease by inhibiting LPS-stimulated cytokine expression (39). This differential response appears to be related both to the stage of apoptosis, with late apoptotic cells generating a stronger inflammatory signal as well as the differentiation state of the phagocytic cell interacting with the C1q-opsonized cell (39).…”

“…Interestingly, C1q can also play a protective role in models of Alzheimer disease by inhibiting LPS-stimulated cytokine expression (39). This differential response appears to be related both to the stage of apoptosis, with late apoptotic cells generating a stronger inflammatory signal as well as the differentiation state of the phagocytic cell interacting with the C1q-opsonized cell (39). Binding of C1q to calreticulin is also linked to the induction of an immunogenic response to apoptotic cells (16).…”

“…These data suggest a strong proinflammatory milieu after ethanol feeding but clearly indicate that there are differences in the immune mileau in adipose tissue after chronic ethanol compared with diet-induced obesity. Given the influence of macrophage phenotype on the interaction between C1q and apoptotic cells observed in mouse brain (39), it will be interesting in future studies to compare the role of C1q in mediating obesity-induced versus ethanol-induced adipose tissue inflammation, particularly in relation to the phenotypic characteristics of the innate immune cells present in adipose tissue.…”