C1q enhances microglial clearance of apoptotic neurons and neuronal blebs, and modulates subsequent inflammatory cytokine production

Abstract

The expression of C1q, a recognition molecule of the complement system, is upregulated following neuronal injury and is detected early in neurodegenerative disorders such as Alzheimer's disease. This multimeric protein triggers an enhancement of phagocytosis of suboptimally opsonized targets by microglia, the phagocytic cells of the CNS, similar to other phagocytes, enhances the uptake of apoptotic cells in peripheral phagocytes, and suppresses inflammatory cytokine production in human monocytes, macrophages and dendritic cells in the absence of activation of the entire complement cascade. The goal of this study was to determine if C1q could influence the inflammatory response to injury in the CNS, using primary rat microglia and neurons. The data show that microglia preferentially ingest apoptotic cells in comparison to live cells, like other professional phagocytes, that microglial ingestion of apoptotic neurons and neuronal blebs is enhanced by the presence of normal serum and that these enhanced levels of uptake are diminished in serum depleted of C1q. In addition, purified C1q bound to apoptotic neurons and neuronal blebs in a dose dependent manner, and alone triggered a significant enhancement of uptake by microglia. Microglia added to C1q coated wells or fed apoptotic neurons or neuronal blebs coated with C1q suppressed the LPS-induced production of proinflammatory cytokines IL-1α, IL-1β, IL-6 and TNF-α, while the presence of C1q enhanced levels of the chemokine MCP-1/CCL2. The data are consistent with a protective role for C1q in the CNS during early stages of cell death by enhancing microglial clearance of apoptotic cells and suppressing proinflammatory cytokines.

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.…”

Functional Complement C1q Abnormality Leads to Impaired Immune Complexes and Apoptotic Cell Clearance

“…Again, both C1q and C3 binding to damaged neurons is required for efficient silent phagocytosis of apoptotic cells (16). Eighteen percent of the C1q-deficient patients presented with neurologic manifestations, as did the patient described in this article (35,39), but no neurolupus was found in C1r-, C1s-, or C4-deficient patients (14).…”

“…Obtained results validated the structural prediction of the importance of this region for the formation of the C1 complex and explained the observed lack of classical pathway activation and C3b deposition on activating surfaces. C3b and its degradation products are of importance for the proper clearance of the apoptotic cells via interaction with CR3 on monocytes, macrophages, and dendritic and microglial cells (12,16). Therefore, GlyB 63 Ser could be classified as a loss of function in terms of complement activation and apoptotic cell opsonization.…”