Mizoguchi Lab: Intestinal Epithelial Cell Homeostasis
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We investigate the basic cellular and molecular mechanisms involved in the functional modulation of colonic epithelial cells (CEC) during the development of inflammatory bowel disease (IBD). Our primary study includes identifying key molecules which regulate CEC/microorganism interaction, CEC/lamina propria cell interaction and intestinal epithelial cell barrier function.
Emiko Mizoguchi, M.D., Ph.D.
Assistant Professor of Medicine, Harvard Medical School
Assistant Immunologist, Department of Medicine, Massachusetts General Hospital
Investigator, Center for the Study of Inflammatory Bowel Disease at Massachusetts General Hospital
Current Lab Members
- Renuka Subramaniam, DVM, Ph.D.
- Rita Kumari, Ph.D.
- Arianna DeGruttola, B.S.
- Barbara Steele - Grant Manager
Former Lab Members
- Daren Low, Ph.D. (A*STAR Graduate Academy, Singapore)
- In-Ah Lee, Ph.D. (JINIS Biopharmaceutical Co., Wanju, South Korea)
- Tsuyoshi Mishiro, M.D. Ph.D. (Shimane Medical University, Simane, Japan)
- Victoria Llado, Ph.D. University of California at San Diego
- Hoa T. Tran, Ph.D. MGH Institute of Health Professions
- Matsuka Murakami, D.V.M., Ph.D. Hokkaido University, Japan
- Chun-Chuan Chen, M.D. Nagasaki University, Japan
- Katsuya Nagatani, M.D., Ph.D. The University of Tokyo, Japan
- Mayumi Kawada, M.D., Ph.D. Kyoto University, Japan
- Yuriko Hachiya, M.D., Ph.D. Toho University, Japan
- Atsuko Arihiro, D.M.D.
Our research group has utilized experimental models of IBD to understand the mechanisms in the pathogenesis of chronic colitis, which include T cell receptor alpha chain knockout (KO) mice, CD45RBhi cell transfer mice, IL-10 KO mice, IL-2 KO mice, and dextran sulfate sodium induced colitis models (Inflamm Bowel Dis, 2003; J Gastroenterol, 2008; Curr Opin Pharmacol, 2010 in press).
My laboratory currently focuses on studying the functional role of the Chitinase 3-like-1 (CHI3L1) molecule in the colonic mucosa (mainly expressed in CEC and macrophages). Our studies have demonstrated that CHI3L1 upregulation is a common factor in intestinal inflammation as indicated by the upregulation of this molecule in acute and chronic colitis models as well as human IBD. The CHI3L1 molecule was upregulated after pro-inflammatory cytokine stimulation and enhanced the adhesion and internalization of intracellular bacteria in epithelial cells. Most importantly, in vivo neutralization of CHI3L1 activity significantly suppressed the development of acute colitis by dramatically decreasing bacterial invasion of the intestinal mucosa. Our present study provides a novel insight into the physiological role of mammalian chitinases in host/microbial interactions (Gastroenterology, 2006; Immunologic Research, 2007; Lab Invest, 2008). We will expand our study of CHI3L1 and other members of mammalian chitinases (e.g., acidic mammalian chitinase and chitotriosidase) in relation to acute and chronic colitis in animal models as well as human IBD.
Furthermore, we propose to test the hypothesis that oral administration of low doses of chitin micro-particles ameliorates intestinal inflammation in both acute and chronic colitis. Chitinase-like molecules are most likely a potential therapeutic target that can be manipulated to control IBD and other forms of inflammatory disorders. Furthermore, it has been reported that CHI3L1 is not synthesized by healthy individuals but shows significantly increased production in the serum of patients with IBD as well as colon cancer (World J Gastroenterol 2009). Utilizing colonic samples obtained from patients with colitis-associated cancer (CAC), a mouse model of CAC and an in vivo experimental system, we are now analyzing the biological function of CHI3L1 in the pathogenesis of IBD and following CAC.
In addition to this major project, our laboratory focuses on the biological function of tumor necrosis factor receptor type-I (TNFR1) and type-II (TNFR2) associated with CEC in colitis. TNFR1 protein is constitutively expressed on wide variety of cell types, but TNFR2 is only expressed on highly activated cells. It has been well characterized that the dual signaling pathways (cell death and cell proliferation) are stimulated by TNFR1 and TNFR2 in T cells. Recently, we have identified that TNFR2 expression is induced on the surface of CEC under inflammatory conditions seen in human IBD as well as several murine models of colitis (Gastroenterology, 2002). Recently, we identified that TNFR1-signaling cascade in colonic myeloid lineage cells contributes to the suppression of acute damage associated mortality by controlling CEC homeostasis (Gastroenterology, 2008). Although it is clear that TNF/TNFRs interactions in T cells play a crucial pathogenic role in colitis, the effects of TNF/TNFRs interactions on CEC function have not been fully defined yet. Our studies will help clarify the distinct roles of TNFRs in the pathogenesis of colitis and providing new therapeutic approach based on the modification of TNF/TNFRs interactions in human IBD.
We strongly believe that our studies will provide novel insight into the mechanisms by which a previously undescribed host/microbial interaction regulates intestinal inflammation.
- Tran HT, Lee IA, Low D, Kamba A, Mizoguchi A, Shi HN, Lee CG, Elias JA, Mizoguchi E. Chitinase 3-like 1 synergistically activates IL6-mediated STAT3 phosphorylation in intestinal epithelial cells in murine models of infectious colitis. Inflammatory Bowel Diseases, 2014; 20: 835-846.
- Liao G, van Driel B, Magelky E, O'Keeffe MS, de Waal Malefyt R, Engel P, Herzog RW, Mizoguchi E, Bhan AK, Terhorst C. Glucocorticoid-induced TNF receptor family-related protein ligand regulates the migration of monocytes to the inflamed intestine. FASEB Journal, 2014; 28:474-484.
- Lee IA, Low D, Kamba A, Llado V, Mizoguchi E. Oral caffeine administration ameliorates acute colitis by suppressing chitinase 3-like 1 expression in intestinal epithelial cells. Journal of Gastroenterology, 2014;49:1206-1216.
- Conway KL, Kuballa P, Song JH, Patel KK, Castoreno AB, Yilmaz OH, Jijon HB, Zhang M, Aldrich LN, Villablanca EJ, Peloquin JM, Goel G, Lee IA, Mizoguchi E, Shi HN, Bhan AK, Shaw SY, Schreiber SL, Virgin HW, Shamji AF, Stappenbeck TS, Reinecker HC, Xavier RJ. Atg16l1 is required for autophagy in intestinal epithelial cells and protection of mice from Salmonella infection. Gastroenterology, 2013; 145:1347-1357.
- Low D, Tran HT, Lee IA, Dreux N, Kamba A, Reinecker HC, Darfeuille-Michaud A, Barnich N, Mizoguchi E. Chitin-binding domains of Escherichia coli ChiA mediate interactions with intestinal epithelial cells in mice with colitis. Gastroenterology, 2013; 145: 602-612.
- Nishida A, Nagahama K, Imaeda H, Ogawa A, Lau CW, Kobayashi T, Hisamatsu T, Preffer FI, Mizoguchi E, Ikeuchi H, Hibi T, Fukuda M, Andoh A, Blumberg RS, Mizoguchi A. Inducible colitis-associated glycome capable of stimulating the proliferation of memory CD4+ T cells. J Exp Med, 2012; 209:2383-2394.
- van Driel B, Liao G, Romero X, O'Keeffe MS, Wang G, Faubion WA, Berger SB, Magelky EM, Manocha M, Azcutia V, Grisham M, Luscinskas FW, Mizoguchi E, de Waal Malefyt R, Reinecker HC, Bhan AK, Wang N, Terhorst C. Signaling lymphocyte activation molecule regulates development of colitis in mice. Gastroenterology, 2012; 143:1544-1554.
- Nagatani K, Wang S, Llado V, Lau CW, Li Z, Mizoguchi A, Nagler CR, Shibata Y, Reinecker HC, Mora JR, Mizoguchi E. Chitin-microparticles for the control of intestinal inflammation. Inflammatory Bowel Diseases, 2012; 18:1698-1710.
- Kawada M, Seno H, Kanda K, Nakanishi Y, Akitake R, Komekado H, Kawada K, Sakai Y, Mizoguchi E, Chiba T. Chitinase 3-like 1 promotes macrophage recruitment and angiogenesis for colorectal cancer development. Oncogene, 2012; 31:3111-3123.
- Nishida A, Lau CW, Zhang M, Andoh A, Shi HN, Mizoguchi E, Mizoguchi A. A membrane-bound mucin Muc1 serves as a negative feedback in colitis-associated Th17 responses. Gastroenterology, 2012; 142: 865-874.
- Chen CC, Pekow J, Llado V, Kanneganti M, Lau CW, Mizoguchi A, Mino-Kenudson M, Bissonnette M, Mizoguchi E. Chitinase 3-like 1 (CHI3L1/YKL-40) expression in colonic epithelial cells as a potentially novel marker for colitis-associated neoplasia. Am J Pathol, 2011, 179:1494-1503.
- Chen CC, Llado V, Eurich K, Tran HT, Mizoguchi E. Carbohydrate-binding motif in chitinase 3-like-1 (CHI3L1/YKL-40) specifically activates Akt signaling pathway in colonic epithelial cells. Clin Immunol, 2011; 140:268-275.
- Tran HT, Barnich N, Mizoguchi E. Potential role of chitinases and chitin-binding proteins in host-microbial interactions during the development of intestinal inflammation. Histol Histopathol, 2011;26:1453-1464.
- Mizoguchi A, Mizoguchi E. Animal models of IBD: linkage to human disease. Curr Opini Pharmacol, 2010;10:578-587.
- Matharu K, Mizoguchi E, Cotoner CA, Nguyen DD, Mingle B, Iweala OI, McBee ME, Stefka AT, Prioult G, Haigis KM, Bhan AK, Snapper SB, Murakami H, Reinecker HC, Mizoguchi A, Nagler CR. Toll-like receptor 4-mediated regulation of spontaneous Helicobacter-dependent colitis in IL-10-deficient mice. Gastroenterology 2009, 137:1380-1390.
- Kawada M, Chen CC, Arihiro A, Nagatani K, Watanabe T, Mizoguchi E. Chitinase 3-like-1 enhances bacterial adhesion to colonic epithelial cells through the interaction with bacterial chitin-binding protein. Lab Invest, 2008;88:883-895.
- Mizoguchi E, Hachiya Y, Kawada M, Nagatani K, Ogawa A, ugimoto K, Mizoguchi A, Podolsky DK. TNF receptor type I-dependent activation of innate responses to reduce intestinal damage-associated mortality. Gastroenterology 2008;134:470-480.
- Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK, Blumberg RS, Xavier RJ, Mizoguchi A. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest 2008;118:524-544.
- Mizoguchi E. Chitinase 3-like-1 exacerbates intestinal inflammation by enhancing bacterial adhesion and invasion in colonic epithelial cells. Gastroenterology 2006;130:398-411.
- Hokama A, Mizoguchi E, Sugimoto K, Shimomura Y, Tanaka Y, Yoshida M, Rietdijk ST, de Jong YP, Snapper SB, Terhorst C, Blumberg RS, Mizoguchi A. Induced reactivity of intestinal CD4+ T cells with an epithelial cell lectin, galectin-4, contributes to exacerbation of intestinal inflammation. Immunity 2004;20:681-693.
- Mizoguchi E, Xavier RJ, Reinecker HC, Uchino H, Bhan AK, Podolsky D, Mizoguchi A. Colonic epithelial functional phenotype varies with type and phase of experimental colitis. Gastroenterology 2003;125:148-61.
- Mizoguchi E, Mizoguchi A, Takedatsu H, Cario E, de Jong YP, Ooi CJ, Xavier RJ, Terhorst C, Podolsky DK, Bhan AK. Role of tumor necrosis factor receptor 2 (TNFR2) in colonic epithelial hyperplasia and chronic intestinal inflammation. Gastroenterology 2002;122:134-144.
- Mizoguchi A, Mizoguchi E, Takedatsu H, Blumberg RS, Bhan AK. Chronic intestinal inflammatory condition generates IL-10 producing regulatory B cell subset characterized by CD1d upregulation. Immunity 2002;16:219-230.
- de Jong YP, Abadia-Molina AC, Satoskar AR, Clarke K, Rietdijk S, Faubion WA, Mizoguchi E, Metz CN, Al Sahli M, ten Hove T, Keates AC, Lubetsky JB, Farrell RJ, Michetti P, van Deventer SJ, Lolis E, David JR, Bhan AK, Terhorst C. Development of chronic colitis is dependent on the cytokine MIF. Nature Immunol 2001;2:1061-1066.
- Hollander GA, Zuklys S, Morel C, Mizoguchi E , Mobbison K Simpson S, Terhorst C, Golan DE, Bhan AK, Burakoff SJ. Monoalleic Expression of the interleukin-2 locus. Science 1998;279:2118-2121.
- Mizoguchi E, Mizoguchi A, Chiba C, Niles JL, Bhan AK. Anti-neutrophil cytoplasmic antibodies producing B cells in TCR a - mutant mice with chronic colitis. Gastroenterology 1997;113:1828-1835.
- Mizoguchi A, Mizoguchi E , Smith RN, Preffer FI, Bhan AK. Suppressive role of B cells in chronic colitis of T cell receptor a mutant mice. J Exp Med 1997;186:1749-1756.
- Mizoguchi E, Mizoguchi A, Bhan AK. Role of cytokines in the early stages of chronic colitis in TCR a -mutant mice. Lab Invest 1997;76:385-397.
- Mizoguchi A, Mizoguchi E , Chiba C, Bhan AK: Role of appendix in the development of inflammatory bowel disease in TCR- a mutant mice. J Exp Med 1996;184:707-715.
- Hollander GA, Simpson SJ, Mizoguchi E , Nichogiannopoulou A, She J, Gutierrez-Ramos J-C, Bhan AK, Burakoff SJ, Wang B, Terhorst C: Severe colitis in mice with abberrant thymic selection. Immunity 1995;3:27-38.
- Mombaert P, Mizoguchi E, Grusby MJ, Glimcher LH, Bhan AK, Tonegawa S: Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice. Cell 1993;75:275-282.