The complement system in neurodegenerative and inflammatory diseases of the central nervous system

Abstract

Neurodegenerative and neuroinflammatory diseases, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis, affect millions of people globally. As aging is a major risk factor for neurodegenerative diseases, the continuous increase in the elderly population across Western societies is also associated with a rising prevalence of these debilitating conditions. The complement system, a crucial component of the innate immune response, has gained increasing attention for its multifaceted involvement in the normal development of the central nervous system (CNS) and the brain but also as a pathogenic driver in several neuroinflammatory disease states. Although complement is generally understood as a liver-derived and blood or interstitial fluid operative system protecting against bloodborne pathogens or threats, recent research, particularly on the role of complement in the healthy and diseased CNS, has demonstrated the importance of locally produced and activated complement components. Here, we provide a succinct overview over the known beneficial and pathological roles of complement in the CNS with focus on local sources of complement, including a discussion on the potential importance of the recently discovered intracellularly active complement system for CNS biology and on infection-triggered neurodegeneration.

Keywords: brain; central nervous system; complement; complosome; development; neurodegeneration; neuroinflammation.

Figure 1

Complement activation, regulation, and functions. Three pathways lead to the formation of C3 and C5 convertases that then cleavage-activate C3 into C3a and C3b, and C5 into C5a and C5b. Assembly of C5b with C6–C9 induces the insertion of the membrane attack complex (MAC) into target membranes while C3b/iC3b opsonizes and tags targets for phagocytic uptake and the anaphylatoxins C3a and C5a mediate the classical inflammatory reactions. The system is controlled by several fluid-phase and membrane-bound complement regulators (red). In circulation, this system detects and removes invading pathogens and noxious antigens. In tissues, C3 and C5 are secreted by immune and non-immune cells, and the extracellularly generated C3 and C5 activation fragments induce cell-specific responses in an autocrine and/or paracrine manner. Intracellularly active complement (the complosome) operates across a broad range of cell populations and at different subcellular locations, where they majorly control basic physiological processes, often in direct crosstalk with other intracellular danger-sensing systems. C1-INH, C1 esterase inhibitor; C3aR, C3a receptor; C5aR, C5a receptor; C4BP, C4b-binding protein; CR1, complement receptor 1; ETC, electron transport chain; FB, factor B; FD, factor D; FH, factor H; FI, factor I; MASP, MBL-associated serine protease; MAVS, mitochondrial antiviral signaling protein; MBL, mannose-binding lectin; mTOR, mechanistic target of rapamycin; OXPHOS, oxidative phosphorylation; RIG-I, retinoic acid-inducible gene I; ROS, reactive oxygen species. Created with BioRender.com.

Figure 2

Cellular sources of complement in the CNS. Depicted are the currently known expression profiles of complement system components by major cells in the CNS. Kolmer’s epiplexus macrophages expressing CR1–CR4 and CD55 and CD59 are not shown. This schematic does not discriminate between complement expression measured on the transcriptional (mRNA) or translational (protein) level and combines data derived from resting CNS cells (steady state) and from cells activated during neuroinflammation. C1-INH, C1 inhibitor; C4BP, C4b-binding protein; cC1qR, receptor for the collagen-like region of C1q; CR1–4, “complement receptors 1–4; F, factor; gC1qR, receptor for the globular head region of C1q; MASP1/2, mannose-binding lectin associated protease 1 or 2; MBL, mannose-binding lectin. ^*C3 and C4 activation fragments can be detected specifically during CNS inflammation or infection and often in proximity to microglia. Created with BioRender.com.

Figure 3

Complement in the CNS—the Good and the Bad. A summary overview over the core beneficial and detrimental activities of complement in the CNS. More detailed information (if available) on the specific molecular mechanisms underlying the depicted complement functions can be found in several recent reviews on this subject matter. A1, neurotoxic, reactive, astrocytes; BBB, blood-brain barrier; DAMP, danger-associated molecular pattern; EC, endothelial cell; MAC, membrane attack complex; MIMS, microglia inflamed in MS; NLRP3, NLR family pyrin domain containing 3. ^*It is currently unclear if the remyelinating capacity of C5aR1 is due to a direct effect on oligodendrocytes or mediated through an indirect effect on other cells. Created with BioRender.com.