Targeting endothelial CD146 attenuates colitis and prevents colitis-associated carcinogenesis.
Recently, enhanced CD146 expression was reported on endothelial cells in intestinal biopsies from patients with inflammatory bowel disease. However, the underlying mechanism remains unknown. Here, we found that overexpressed endothelial CD146 promoted the inflammatory responses in inflammatory bowel disease, which further potentiated the occurrence of colitis-associated colorectal carcinogenesis. Eliminating endothelial CD146 by conditional knockout significantly ameliorated the severity of inflammation in two different murine models of colitis, and decreased tumor incidence and tumor progression in a murine model of colitis-associated colorectal carcinogenesis. Mechanistic study showed that cytokine tumor necrosis factor-α (TNF-α) up-regulated the expression of endothelial CD146 through NF-κB transactivation. In turn, the enhanced endothelial CD146 expression promoted both angiogenesis and proinflammatory leukocyte extravasations, contributing to inflammation. Using an anti-CD146 antibody, AA98, alone or together with an anti-TNF-α antibody significantly attenuated colitis and prevented colitis-associated colorectal carcinogenesis in mice. Our study provides the first evidence that CD146 plays a dual role on endothelium, facilitating leukocyte extravasations and angiogenesis, thus promoting inflammation. This finding not only reveals the function and regulating mechanism of CD146 in inflammatory bowel disease, but also provides a promising therapeutic strategy for treating inflammatory bowel disease and preventing colitis-associated colorectal carcinogenesis.
Key Laboratory of Protein and Peptide Pharmaceuticals, Center for Infection and Immunity, and the Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Shu
S
Xing
Key Laboratory of Protein and Peptide Pharmaceuticals, Center for Infection and Immunity, and the Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Yongting
Y
Luo
Key Laboratory of Protein and Peptide Pharmaceuticals, Center for Infection and Immunity, and the Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Zhihua
Z
Liu
Key Laboratory of Protein and Peptide Pharmaceuticals, Center for Infection and Immunity, and the Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Pengcheng
P
Bu
Key Laboratory of Protein and Peptide Pharmaceuticals, Center for Infection and Immunity, and the Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Hongxia
H
Duan
Key Laboratory of Protein and Peptide Pharmaceuticals, Center for Infection and Immunity, and the Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Dan
D
Liu
Key Laboratory of Protein and Peptide Pharmaceuticals, Center for Infection and Immunity, and the Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Ping
P
Wang
Department of Gastroenterology, Chinese PLA General Hospital, Beijing, China.
Jing
J
Yang
Key Laboratory of Protein and Peptide Pharmaceuticals, Center for Infection and Immunity, and the Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Lina
L
Song
Key Laboratory of Protein and Peptide Pharmaceuticals, Center for Infection and Immunity, and the Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Jing
J
Feng
Key Laboratory of Protein and Peptide Pharmaceuticals, Center for Infection and Immunity, and the Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Dongling
D
Yang
Key Laboratory of Protein and Peptide Pharmaceuticals, Center for Infection and Immunity, and the Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Zhihai
Z
Qin
Key Laboratory of Protein and Peptide Pharmaceuticals, Center for Infection and Immunity, and the Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. Electronic address: yanxy@ibp.ac.cn.
Xiyun
X
Yan
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D051929:CD146 Antigen / Q000378:metabolism*; D063646:Carcinogenesis / Q000473:pathology*; D002450:Cell Communication / Q000187:drug effects; D003092:Colitis / Q000473:pathology* / Q000517:prevention & control*; D015179:Colorectal Neoplasms / Q000473:pathology / Q000517:prevention & control; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000473:pathology; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000906:Antibodies; D051929:CD146 Antigen; D053583:Interleukin-1beta; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate