Local complement activation and modulation in mucosal immunity

Abstract

The complement system is an evolutionarily conserved arm of innate immunity, which forms one of the first lines of host response to pathogens and assists in the clearance of debris. A deficiency in key activators/amplifiers of the cascade results in recurrent infection, whereas a deficiency in regulating the cascade predisposes to accelerated organ failure, as observed in colitis and transplant rejection. Given that there are over 60 proteins in this system, it has become an attractive target for immunotherapeutics, many of which are United States Food and Drug Administration-approved or in multiple phase 2/3 clinical trials. Moreover, there have been key advances in the last few years in the understanding of how the complement system operates locally in tissues, independent of its activities in circulation. In this review, we will put into perspective the abovementioned discoveries to optimally modulate the spatiotemporal nature of complement activation and regulation at mucosal surfaces.

Keywords: ATG7; C3 F/S; C3 fast/slow; CCAAT; CXCL; DSS; FXR; HSV-1; ICAM; IRF; JAK1/2; Janus kinase ½; MAPK; MMP; NLRP3; PPAR; PTEN; RELA - v-rel; ROS; STAT1; VEGF-A; autophagy related 7; chemokine (C-X-C motif) ligand; cytosine-cytosine-adenosine-adenosine-thymidine; dextran sodium sulfate; farnesoid X receptor; herpes simplex virus-1; intercellular adhesion molecule; interferon regulatory factor; matrix metalloproteinase; mitogen-activated protein kinase; nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3; peroxisome proliferator-activated receptor; phosphatase and tensin homolog; reactive oxygen species; reticuloendotheliosis viral oncogene homolog A (avian); signal transducer and activation of transcription 1; vascular endothelial growth factor-A.

Figure 1.. The complement cascade and its regulation.

The complement cascade can be initiated by either the classical pathway, primarily through antigen-antibody complexes; the lectin pathway when pattern recognition molecules such as ficolins (FCN) and mannose-binding lectin (MBL) bind to sugars, or through alternative pathway activation, which occurs via spontaneous tickover, but is amplified by properdin (P). These pathways converge on the formation of C3 convertases, which can cleave C3 to C3a and C3b. C3b facilitates formation of C5 convertases, which can cleave C5 into C5a and C5b. C5b forms complexes with C6, C7, C8 and C9 to form the membrane attack complex (MAC). At each step, the complement cascade is tightly regulated by fluid-phase regulators (AT: antithrombin; C1-INH: C1 inhibitor; C1QBP: C1q binding protein; C4BP: C4 binding protein; CLU: clusterin; CPN: carboxypeptidase N; CSMD1: CUB And Sushi Multiple Domains 1; FH: Factor H, FI: Factor I; VTN: vitronectin) and membrane regulators (CD46; CD55; CD59; CR1; VSIG4: VSIG4 V-set and immunoglobulin domain containing 4).

Figure 2.. Complement-mediated host defense in the lung.

In the lung, structural and immune cells are local sources of complement, in addition to the circulating proteins that leak into the lungs during injury. Complement plays multiple roles in the host immune response and in maintaining homeostasis. Within lung cells, C3 is synthesized and cleaved into C3a and C3b. C3b plays a role in opsonizing pathogens to facilitate phagocytosis. It also initiates inflammation by binding to the receptor for C3a (C3aR), leading to the expression of cytokines such as TNF-α and IL-1β. Additionally, C3b participates in facilitating membrane attack complex (MAC) formation by serving as part of the C5 convertase, which cleaves C5 into C5a and C5b. C5b forms a part of the MAC, resulting in cellular lysis. Furthermore, C3a and C5a act as anaphylatoxins, recruiting leukocytes to the site of infection. Intracellular mitochondrial, lysosomal, and/or endosomal C3aR and C5aR1 execute their functions by initiating signaling cascades like those initiated extracellularly.

Figure 3.. The role of gut-derived complement.

There is growing recognition that complement proteins play an important role in shaping the gut microbiome. During early life, newborn pups receive complement (for example, C3) from breast milk. The presence of complement proteins in the breast milk is critical to limit the bloom of gram-positive bacteria, such as Staphylococcus lentus B3, and is critical for providing protection from enteric pathogens such as Citrobacter rodentium. In fully grown adult mice during homeostasis, the gut microbiome influences the production of certain complement factors, such as C3 from stromal cells. This stromal cell-derived C3 is also critical to fight infection from Citrobacter rodentium. In animal models of chronic intestinal inflammation, gram-negative bacteria trigger TLR4 and C3 expression in colonic epithelial cells, which gets secreted in the lumen to affect the bacterial composition.