Neuroprotective versus Neuroinflammatory Roles of Complement: From Development to Disease

Abstract

Complement proteins are ancient components of innate immunity that have emerged as crucial regulators of neural networks. We discuss these roles in the context of the CNS development, acute CNS viral infections, and post-infectious and noninfectious CNS disorders, with an emphasis on microglia-mediated loss of synapses. Despite extensive examples that implicate classical complement proteins and their receptors in CNS dysfunction, recent data suggest that they exert neuroprotective roles in CNS homeostasis through continued refinement of synaptic connections. Thorough understanding of the mechanisms involved in these processes may lead to novel targets for the treatment of CNS diseases involving aberrant complement-mediated synapse loss.

Keywords: astrocytes; microglia; neurodegenerative disease; synapse; viral encephalitis.

Figure 1:. Complement Pathways.

The complement system is divided into three pathways: Classical, lectin, and alternative. The classical pathway is initiated by antigen-antibody complexes by C1qrs. The lectin pathway is initiated by mannose binding lectin (MBL) binding to sugar monomers (mannose) on pathogen surfaces. The alternative pathway is initiated by the spontaneous hydrolysis of C3 into active components. Through a series of enzymatic steps that produces the C3 convertase (C4b2b or C3bBb), each pathway converges to the cleavage of C3 into active components C3a and C3b. C3b then produces C5 convertases (C4b2b3b or C3bBb3b), which cleaves C5 into active components C5a, and C5b. Through the combination of C5b-C9 the membrane attack complex is formed and is able to produce pores in targeted cells or pathogens, resulting in lysis. Furthermore, anaphylatoxins (C3a and C5a) function as chemoattractants and recruit immune cells to sites of injury.

Figure 2:. Complement signaling in neurodegeneration and neuro-infection.

There is evidence of complement expression on astrocytes, microglia, neurons, and oligodendrocytes following either neuro-infection or neurodegeneration. In neurodegeneration, classical complement components are expressed on all 4 cell types, and activation leads to synapse elimination, increased neuroinflammation and changes in dendritic morphology. In neuro-infection, components are expressed on neurons and microglia, and activation leads to synapse elimination. Interestingly, C3-CR3 signaling contributes to synapse elimination in neurodegeneration, whereas C3-C3aR signaling leads to synapse elimination in neuro-infection. Modulators of complement during neurodegeneration include cytokines, progranulin, TREM2, ApoE [, , –109].

Figure 3:. Complement as a biomarker of human CNS disease.

Complement proteins increase or decrease in CSF levels during CNS disease progression. In AD patients CSF C3 levels decrease in more severe disease [–104]. After TBI injury, studies show increases in C1q and C3 in human CSF [–99]. Similar trends are seen in other autoimmune CNS diseases such as MS, where C1q and C3 increases correspond with more severe disease and disability [–105]. After infection from TBEV, and HIV patients have increased CSF complement expression (TBEV-C1q, C3a, C3b, C5a) (HIV-C1q) compared to healthy controls [–97].