Madcam1, short for mucosal addressin cell adhesion molecule 1, encodes an immunoglobulin family vascular addressin. It controls lymphocyte homing into intestinal tissues by decorating endothelial cells lining gut post-capillary and high endothelial venules, thus regulating immunity and inflammation. Its expression is directed by an NKX-COUP-TFII morphogenetic code [7].

In cancer, the down-regulation of Madcam1 in the ileum due to post-antibiotic gut recolonization by Enterocloster species drives the emigration of enterotropic α4β7+CD4+ regulatory T 17 cells into the tumor. Genetic deficiency or antibody-mediated neutralization of Madcam1 and its receptor, α4β7 integrin, mimicked the immunosuppressive effects of antibiotics, indicating Madcam1's role in cancer immunosurveillance [1].

In colitis, optogenetic activation of local colonic sympathetic innervations attenuated experimental colitis by decreasing endothelial expression of Madcam1, and antibody blockade of Madcam1 abrogated the optogenetic effect on immune cell extravasation and pathology [2].

In acute liver failure, hepatic Madcam1 levels were induced and positively correlated with liver damage. Activating the cholinergic anti-inflammatory pathway downregulated Madcam1 and inhibited gut-derived proinflammatory lymphocytes infiltration [3].

In glaucoma, retinal endothelial cell expression of Madcam1 was elicited by β7+ CD4+ T cells, and neutralization with an Madcam1 antibody ameliorated retinal ganglion cell loss [4].

In Crohn's disease, treatment with anti-TNF-α reduced the number of Madcam1-positive mucosal capillaries [5].

In hepatocellular carcinoma cells, Madcam1 overexpression suppressed, while depletion stimulated doxorubicin-induced apoptosis [6].

In melanoma, knockdown of Madcam1 impeded epithelial-mesenchymal transition and inhibited tumor growth and metastasis [8].

In checkpoint inhibitor colitis, endothelial cells upregulated Madcam1, which may preferentially respond to vedolizumab [9].

In summary, Madcam1 is crucial for lymphocyte homing and immune regulation. Studies using gene knockout or antibody-mediated neutralization models have revealed its significant roles in various disease conditions such as cancer, colitis, liver failure, glaucoma, Crohn's disease, hepatocellular carcinoma, melanoma, and checkpoint inhibitor colitis, providing potential therapeutic targets for these diseases.

References:

1. Fidelle, Marine, Rauber, Conrad, Alves Costa Silva, Carolina, Kroemer, Guido, Zitvogel, Laurence. 2023. A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers. In Science (New York, N.Y.), 380, eabo2296. doi:10.1126/science.abo2296. https://pubmed.ncbi.nlm.nih.gov/37289890/

2. Schiller, Maya, Azulay-Debby, Hilla, Boshnak, Nadia, Hakim, Fahed, Rolls, Asya. 2021. Optogenetic activation of local colonic sympathetic innervations attenuates colitis by limiting immune cell extravasation. In Immunity, 54, 1022-1036.e8. doi:10.1016/j.immuni.2021.04.007. https://pubmed.ncbi.nlm.nih.gov/33932356/

3. Fu, Shan, Ni, TianZhi, Zhang, MengMeng, Zhao, YingRen, Liu, JinFeng. 2023. Cholinergic Anti-inflammatory Pathway Attenuates Acute Liver Failure Through Inhibiting MAdCAM1/α4β7-mediated Gut-derived Proinflammatory Lymphocytes Accumulation. In Cellular and molecular gastroenterology and hepatology, 17, 199-217. doi:10.1016/j.jcmgh.2023.10.012. https://pubmed.ncbi.nlm.nih.gov/37926366/

4. He, Chong, Xiu, Wenbo, Chen, Qinyuan, Yu, Ling, Lu, Fang. 2023. Gut-licensed β7+ CD4+ T cells contribute to progressive retinal ganglion cell damage in glaucoma. In Science translational medicine, 15, eadg1656. doi:10.1126/scitranslmed.adg1656. https://pubmed.ncbi.nlm.nih.gov/37531415/

5. Younes, Mamoun, DuPont, Andrew W, Cash, Brooks D, Ertan, Atilla. . Alterations in MAdCAM1-Positive Mucosal Capillaries and Integrin a4b7-Positive Lymphocytes in Crohn's Disease Treated with Anti-TNFα Biologics. In Annals of clinical and laboratory science, 51, 678-685. doi:. https://pubmed.ncbi.nlm.nih.gov/34686510/

6. Wang, Jiayi, Ma, Lifang, Tang, Xun, Yu, Yongchun, Sun, Fenyong. . Doxorubicin induces apoptosis by targeting Madcam1 and AKT and inhibiting protein translation initiation in hepatocellular carcinoma cells. In Oncotarget, 6, 24075-91. doi:. https://pubmed.ncbi.nlm.nih.gov/26124182/

7. Dinh, Thanh Theresa, Xiang, Menglan, Rajaraman, Anusha, Pan, Junliang, Butcher, Eugene C. 2022. An NKX-COUP-TFII morphogenetic code directs mucosal endothelial addressin expression. In Nature communications, 13, 7448. doi:10.1038/s41467-022-34991-2. https://pubmed.ncbi.nlm.nih.gov/36460642/

8. Tian, Yuan, Guo, Yantong, Zhu, Pei, Li, Guiying, Zhu, Xun. 2019. TRIM59 loss in M2 macrophages promotes melanoma migration and invasion by upregulating MMP-9 and Madcam1. In Aging, 11, 8623-8641. doi:10.18632/aging.102351. https://pubmed.ncbi.nlm.nih.gov/31600735/

9. He, Jun Yan, Kim, Yang-Joon, Mennillo, Elvira, Kattah, Michael G, Oh, David Y. 2024. Dysregulation of CD4+ and CD8+ resident memory T, myeloid, and stromal cells in steroid-experienced, checkpoint inhibitor colitis. In Journal for immunotherapy of cancer, 12, . doi:10.1136/jitc-2023-008628. https://pubmed.ncbi.nlm.nih.gov/38642938/