Complement activation promotes colitis-associated carcinogenesis through activating intestinal IL-1β/IL-17A axis.
Colitis-associated colorectal cancer (CAC) is the most serious complication of inflammatory bowel disease (IBD). Excessive complement activation has been shown to be involved in the pathogenesis of IBD. However, its role in the development of CAC is largely unknown. Here, using a CAC model induced by combined administration of azoxymethane (AOM) and dextran sulfate sodium (DSS), we demonstrated that complement activation was required for CAC pathogenesis. Deficiency in key components of complement (e.g., C3, C5, or C5a receptor) rendered tumor repression in mice subjected to AOM/DSS. Mechanistic investigation revealed that complement ablation dramatically reduced proinflammatory cytokine interleukin (IL)-1β levels in the colonic tissues that was mainly produced by infiltrating neutrophils. IL-1β promoted colon carcinogenesis by eliciting IL-17 response in intestinal myeloid cells. Furthermore, complement-activation product C5a represented a potent inducer for IL-1β in neutrophil, accounting for downregulation of IL-1β levels in the employed complement-deficient mice. Overall, our study proposes a protumorigenic role of complement in inflammation-related colorectal cancer and that the therapeutic strategies targeting complement may be beneficial for the treatment of CAC in clinic.
Department of Immunology, Institute of Basic Medical Sciences, Beijing, China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.
C
C
Ning
Institute of Immunology, Medical School of Henan University, Kaifeng, China.
Y-Y
YY
Li
Department of Immunology, Institute of Basic Medical Sciences, Beijing, China.
Y
Y
Wang
Department of Immunology, Institute of Basic Medical Sciences, Beijing, China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.
G-C
GC
Han
Department of Immunology, Institute of Basic Medical Sciences, Beijing, China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.
R-X
RX
Wang
Department of Immunology, Institute of Basic Medical Sciences, Beijing, China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.
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H
Xiao
Department of Immunology, Institute of Basic Medical Sciences, Beijing, China.
X-Y
XY
Li
Department of Immunology, Institute of Basic Medical Sciences, Beijing, China.
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CM
Hou
Institute of Immunology, Medical School of Henan University, Kaifeng, China.
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YF
Ma
Department of Thoracic surgery, 307 Hospital of PLA, Beijing, China.
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DS
Sheng
Department of Immunology, Institute of Basic Medical Sciences, Beijing, China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.
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BF
Shen
Department of Immunology, Institute of Basic Medical Sciences, Beijing, China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.
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JN
Feng
Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
R-F
RF
Guo
Department of Immunology, Institute of Basic Medical Sciences, Beijing, China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.
Y
Y
Li
Department of Immunology, Institute of Basic Medical Sciences, Beijing, China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.
G-J
GJ
Chen
D000818:Animals; D063646:Carcinogenesis / Q000276:immunology*; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000378:metabolism; D003092:Colitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D003167:Complement Activation / Q000502:physiology*; D018450:Disease Progression; D005434:Flow Cytometry; D015151:Immunoblotting; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology
C587672:IL1B protein, mouse; D020381:Interleukin-17; D053583:Interleukin-1beta