Complement, c1q, and c1q-related molecules regulate macrophage polarization

Abstract

Complement is a critical system of enzymes, regulatory proteins, and receptors that regulates both innate and adaptive immune responses. Natural mutations in complement molecules highlight their requirement in regulation of a variety of human conditions including infectious disease and autoimmunity. As sentinels of the immune system, macrophages are specialized to respond to infectious microbes, as well as normal and altered self, and dictate appropriate immune responses. Complement components such as anaphylatoxins (C3a and C5a) and opsonins [C3b, C1q, mannan binding lectin (MBL)] influence macrophage responses. While anaphylatoxins C3a and C5a trigger inflammasome activation, opsonins such as C1q and related molecules (MBL and adiponectin) downregulate inflammasome activation and inflammation, and upregulate engulfment of apoptotic cells consistent with a pro-resolving or M2 macrophage phenotype. This review summarizes our current understanding of the influence of the complement system on macrophage polarization with an emphasis on C1q and related molecules.

Keywords: C1q; adiponectin; complement; cytokine; efferocytosis; inflammasome; macrophage; phagocytosis.

Figure 1

The interaction of macrophages with complement. Innate immune pattern recognition receptors C1q, MBL, and ficolins recognize a number of structures including immune complexes, damaged-self molecules expressing damage associated molecular patterns (DAMPS), apoptotic cells (ACAMPs), and pathogens (PAMPs), leading to activation of classical and lectin pathways, respectively, and amplification via the alternative pathway. Complement activation has three main effector functions: cytolysis via membrane attack complex (MAC) formation, inflammation mediated by anaphylatoxins C3a and C5a, and opsonization leading to phagocyte clearance via C3b deposition. However, C1q, MBL, and ficolins also have non-cascade activation related functions and are directly opsonic, leading to enhanced clearance of targets and phagocyte activation. Macrophages express a number of receptors that recognize complement components. The gC1qR and cC1qR bind the globular heads and collagen-like tail domains of C1q, respectively. However, additional C1q receptors likely exist (C1qR), some of which may also recognize the closely related collagen-like domains of other defense collagen family members, MBL and ficolins. Additional complement receptors on macrophages CR1, CR3, CR4, and CRIg recognize C3b-opsonized targets either as intact C3b or its degradation fragment iC3b. Macrophages also express receptors for complement activation fragments C3a (C3aR) and C5a (C5aR1 and C5aR2). Thus, macrophages are key players in carrying out the effector functions of complement activation.

Figure 2

Complement regulates macrophage polarization. In culture, M1 macrophages (inflammatory, pathogen clearing) are induced by IFNγ or PAMPs and are characterized by production of iNOS and pro-inflammatory cytokines such as TNFα and IL-1β. M2 macrophages (resolving, apoptotic cell and damaged molecule clearing) are induced by IL-4 and characterized by arginase and anti-inflammatory cytokine IL-10 production. Complement components C3a, C5a, and C5b-9 modulate cytokine production in macrophages toward an inflammatory (M1-like) phenotype. Apoptotic cells and targets opsonized with complement components C1q or C3b increase clearance and modulate cytokine production in macrophages toward an anti-inflammatory, resolving (M2-like) phenotype and can block PAMP-mediated pro-inflammatory signaling. Thus, complement plays a dual role in macrophage activation and polarization depending on the target.