The complement system in intestinal inflammation and cancer
Carsten Krieg, Silvia Guglietta
Carsten Krieg, Silvia Guglietta
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Review Series

The complement system in intestinal inflammation and cancer

Abstract

The complement system has emerged as a critical regulator of intestinal homeostasis, inflammation, and cancer. In this Review, we explore the multifaceted roles of complement in the gastrointestinal tract, highlighting its canonical and noncanonical functions across intestinal epithelial and immune cells. Under homeostatic conditions, intestinal cells produce complement that maintains barrier integrity and modulates local immune responses, but complement dysregulation contributes to intestinal inflammation and promotes colon cancer. We discuss recent clinical and preclinical studies to provide a cohesive overview of how complement-mediated modulation of immune and nonimmune cell functions can protect or exacerbate inflammation and colon cancer development. The complement system plays a dual role in the intestine, with certain components supporting tissue protection and repair and others exacerbating inflammation. Intriguingly, distinct complement pathways modulate colon cancer progression and response to therapy, with novel findings suggesting that the C3a/C3aR axis constrains early tumor development but may limit antitumor immunity. The recent discovery of intracellular complement activation and tissue-specific complement remains vastly underexplored in the context of intestinal inflammation and colon cancer. Collectively, complement functions are context- and cell-type-dependent, acting both as a shield and a sword in intestinal diseases. Future studies dissecting the temporal and spatial dynamics of complement are essential for leveraging its potential as a biomarker and therapeutic in colon cancer.

Authors

Carsten Krieg, Silvia Guglietta

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Figure 3

Complement in healthy colon, IBD, and colon cancer.

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Complement in healthy colon, IBD, and colon cancer. (A) In healthy colon...
(A) In healthy colon local C3 production is dependent on the commensal flora, and stromal and myeloid cells are the major producers (23). IECs constitutively produce and secrete C3 and express the C3aR and TLR1–4. C3a and its degradation product C3a-DesArg have potent antibacterial and antifungal properties independent of their interaction with C3aR (134). Primary IECs do not express C5aR, indicating that C5aR expression may be more prominent during intestinal inflammation (135, 136). Lgr5+ stem cells in the SI express C3aR, which acts as an autocrine growth factor necessary for the proliferation of the intestinal organoids (137). C3aR is mostly expressed in lamina propria eosinophils, CD11b+ and CD103+ conventional dendritic cells, plasmacytoid dendritic cells, and a fraction of innate lymphoid cells (138). Tregs, macrophages, and dendritic cells support intestinal homeostasis. (B) In inflammatory bowel disease, the reduced mucus layer enables proliferation of pathobionts and their proximity to the intestinal epithelium, causing migration of innate and adaptive immune cells, inflammation and disruption of the intestinal barrier. C3 activation leads to opsonization of mucosa-associated bacteria by C3b. Crohn’s disease involves Th1/Th17 inflammation and higher levels of C3, C1q, and CfB. Ulcerative colitis results in Th2 inflammation and no induction of C3. (C) Alterations of the mucus layers and microbiota occur in colon cancer. Untreated tumors express CD55 and C5aR. Inflammasome activation results in cleavage of C1qbp, preventing its translocation to the mitochondria, inhibiting OXPHOS, and supporting cancer cell proliferation. C5aR-expressing neutrophils produce IL-1β, which stimulates macrophage IL-17 production. C3aR on neutrophils induces NETosis. Both mechanisms support tumor growth. Radiation therapy induces C5aR overexpression on cancer cells. Treatment with a C5aR antagonist causes tumor cell death and improved response to radiotherapy. Loss of C3aR results in increased recruitment of Th1, Th17, and cytotoxic CD8 cells and improved response to anti–PD-1 therapy.