C1q and central nervous system disorders

Abstract

C1q is a crucial component of the complement system, which is activated through the classical pathway to perform non-specific immune functions, serving as the first line of defense against pathogens. C1q can also bind to specific receptors to carry out immune and other functions, playing a vital role in maintaining immune homeostasis and normal physiological functions. In the developing central nervous system (CNS), C1q functions in synapse formation and pruning, serving as a key player in the development and homeostasis of neuronal networks in the CNS. C1q has a close relationship with microglia and astrocytes, and under their influence, C1q may contribute to the development of CNS disorders. Furthermore, C1q can also have independent effects on neurological disorders, producing either beneficial or detrimental outcomes. Most of the evidence for these functions comes from animal models, with some also from human specimen studies. C1q is now emerging as a promising target for the treatment of a variety of diseases, and clinical trials are already underway for CNS disorders. This article highlights the role of C1q in CNS diseases, offering new directions for the diagnosis and treatment of these conditions.

Keywords: c1q; central nervous system; degenerative diseases; glioma; inflammatory diseases; neurodevelopment.

Figure 1

C1q is involved in the immune process. Upon antigen-antibody binding, C1q is activated and subsequently activates C1r and C1s, leading to the formation of C3 convertase C4b2a, C5 convertase C4b2a3b, and ultimately the formation of the membrane attack complex with the involvement of C6 to C9. The globular domain or collagen-like tail of C1q binds to cell surface receptors to produce various physiological effects. The globular domain of C1q binds to SIGN/gC1qR, which regulates the differentiation of immature dendritic cells (3, 4). The tail of C1q binds to the phagocyte surface receptor CR1, promoting the phagocytosis of pathogens (5). Additionally, the globular domain of C1q interacts with the phagocyte surface receptor CRT to promote phagocytosis of apoptotic cells, while binding to gC1qR on the surface of apoptotic cells induces phagocytosis (6, 7). Furthermore, C1q interacts with phagocytes and endothelial cells, increasing cytokine secretion (8, 9).

Figure 2

Mechanism of C1q in nervous system diseases. (A) Activation of glutamatergic neuronal mGluR1 receptors leads to increased expression of C1q mRNA (43). (B) The mGluR5 silent alteration modulator (SAM) inhibits C1q-mediated microglial phagocytosis (44). (C) The ubiquitin ligase COP1 regulates the transcription process of microglial inflammatory genes by controlling CCAAT/enhancer binding protein β (c/EBPβ) (45). (D) LPS (lipopolysaccharide) can bind to TLR4 receptors on microglia, triggering the secretion of C1q, Il-1α, and TNFα by microglia, and inducing A1 in astrocytes (46). (E) C1q prevents the differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes by inhibiting the Wnt/β-catenin signaling pathway (47). (F) C1q interacts with MAG to reduce MAG inhibitory effect on neuronal signals, thereby promoting axonal growth (48). (G) The binding of ApoE to C1q inhibits the initiation of the classical complement cascade reaction (20).