Regenerating Islet-derived Protein (Reg)3β Plays a Crucial Role in Attenuation of Ileitis and Colitis in Mice

Overview

Journal Biochem Biophys Rep

Specialty Biochemistry

Date 2020 Feb 20

PMID 32072024

Citations 7

Authors

Ryodai Shindo

Takaharu Katagiri

Sachiko Komazawa-Sakon

Masaki Ohmuraya

Wakami Takeda

Yoshiko Nakagawa

Naomi Nakagata

Tetsushi Sakuma

Takashi Yamamoto

Chiharu Nishiyama

Takashi Nishina

Soh Yamazaki

Hideto Kameda

Hiroyasu Nakano

Affiliations

Soon will be listed here.

Abstract

Regenerating islet-derived protein (Reg)3β belongs to a member of the Reg family of proteins and has pleiotropic functions, including antimicrobial activity and tissue repair. However, whether Reg3β plays a protective role in the development of colitis and ileitis has not been fully investigated. We generated transgenic mice expressing a short form of cellular FLICE-inhibitory protein (cFLIPs) that promotes necroptosis, a regulated form of cell death. cFLIPs transgenic ( Tg) mice develop severe ileitis in utero. Although Reg3β is undetectable in the small intestine of wild-type embryos, its expression is aberrantly elevated in the small intestine of Tg embryos. To test whether elevated Reg3β attenuates or exacerbates ileitis in Tg mice, we generated a strain. mice grew to adulthood without apparent abnormalities. Deletion of in Tg mice exacerbated the embryonic lethality of Tg mice. Dextran sulfate sodium-induced colitis, characterized by body weight loss and infiltration of neutrophils, was exacerbated in compared to wild-type mice. Moreover, the expression of , an inflammatory cytokine and , a marker for tissue repair macrophages was elevated in the colon of mice compared to wild-type mice after DSS treatment. Together, these results suggest that attenuation of colitis and ileitis is a result of Reg3β's real function.

Citing Articles

Non-stem cell lineages as an alternative origin of intestinal tumorigenesis in the context of inflammation.

Verhagen M, Joosten R, Schmitt M, Valimaki N, Sacchetti A, Rajamaki K Nat Genet. 2024; 56(7):1456-1467.

PMID: 38902475 PMC: 11250264. DOI: 10.1038/s41588-024-01801-y.

Distal colonocytes targeted by C. rodentium recruit T-cell help for barrier defence.

Zindl C, Wilson C, Chadha A, Duck L, Cai B, Harbour S Nature. 2024; 629(8012):669-678.

PMID: 38600382 PMC: 11096101. DOI: 10.1038/s41586-024-07288-1.

Evidence that the loss of colonic anti-microbial peptides may promote dysbiotic Gram-negative inflammaging-associated bacteria in aging mice.

Forsyth C, Shaikh M, Engen P, Preuss F, Naqib A, Palmen B Front Aging. 2024; 5:1352299.

PMID: 38501032 PMC: 10945560. DOI: 10.3389/fragi.2024.1352299.

Milk Fat Globule Membrane Attenuates Acute Colitis and Secondary Liver Injury by Improving the Mucus Barrier and Regulating the Gut Microbiota.

Wu Z, Liu X, Huang S, Li T, Zhang X, Pang J Front Immunol. 2022; 13:865273.

PMID: 35799795 PMC: 9253277. DOI: 10.3389/fimmu.2022.865273.

Mechanisms of mucosal healing: treating inflammatory bowel disease without immunosuppression?.

Villablanca E, Selin K, Hedin C Nat Rev Gastroenterol Hepatol. 2022; 19(8):493-507.

PMID: 35440774 DOI: 10.1038/s41575-022-00604-y.

References

Budd R, Yeh W, Tschopp J . cFLIP regulation of lymphocyte activation and development. Nat Rev Immunol. 2006; 6(3):196-204. DOI: 10.1038/nri1787. View

Montaldo E, Juelke K, Romagnani C . Group 3 innate lymphoid cells (ILC3s): Origin, differentiation, and plasticity in humans and mice. Eur J Immunol. 2015; 45(8):2171-82. DOI: 10.1002/eji.201545598. View

Lim J, Golden J, Ford H . Pathogenesis of neonatal necrotizing enterocolitis. Pediatr Surg Int. 2015; 31(6):509-18. DOI: 10.1007/s00383-015-3697-9. View

Pasparakis M, Vandenabeele P . Necroptosis and its role in inflammation. Nature. 2015; 517(7534):311-20. DOI: 10.1038/nature14191. View

Van Ampting M, Loonen L, Schonewille A, Konings I, Vink C, Iovanna J . Intestinally secreted C-type lectin Reg3b attenuates salmonellosis but not listeriosis in mice. Infect Immun. 2012; 80(3):1115-20. PMC: 3294648. DOI: 10.1128/IAI.06165-11. View

Tanner S, Berryhill T, Ellenburg J, Jilling T, Cleveland D, Lorenz R . Pathogenesis of necrotizing enterocolitis: modeling the innate immune response. Am J Pathol. 2014; 185(1):4-16. PMC: 4278236. DOI: 10.1016/j.ajpath.2014.08.028. View

Yuan J . Divergence from a dedicated cellular suicide mechanism: exploring the evolution of cell death. Mol Cell. 2006; 23(1):1-12. DOI: 10.1016/j.molcel.2006.06.008. View

Murray P, Allen J, Biswas S, Fisher E, Gilroy D, Goerdt S . Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014; 41(1):14-20. PMC: 4123412. DOI: 10.1016/j.immuni.2014.06.008. View

Zhang Y, Ding L, Lai M . Reg gene family and human diseases. World J Gastroenterol. 2003; 9(12):2635-41. PMC: 4612022. DOI: 10.3748/wjg.v9.i12.2635. View

10.

Takasawa S, Tsuchida C, Sakuramoto-Tsuchida S, Takeda M, Itaya-Hironaka A, Yamauchi A . Expression of human REG family genes in inflammatory bowel disease and their molecular mechanism. Immunol Res. 2019; 66(6):800-805. DOI: 10.1007/s12026-019-9067-2. View

11.

Matsumoto S, Konishi H, Maeda R, Kiryu-Seo S, Kiyama H . Expression analysis of the regenerating gene (Reg) family members Reg-IIIβ and Reg-IIIγ in the mouse during development. J Comp Neurol. 2011; 520(3):479-94. DOI: 10.1002/cne.22705. View

12.

Parikh A, Stephan A, Tzanakakis E . Regenerating proteins and their expression, regulation and signaling. Biomol Concepts. 2012; 3(1):57-70. PMC: 3348543. DOI: 10.1515/bmc.2011.055. View

13.

Gironella M, Calvo C, Fernandez A, Closa D, Iovanna J, Rosello-Catafau J . Reg3β deficiency impairs pancreatic tumor growth by skewing macrophage polarization. Cancer Res. 2013; 73(18):5682-94. DOI: 10.1158/0008-5472.CAN-12-3057. View

14.

Weinlich R, Oberst A, Beere H, Green D . Necroptosis in development, inflammation and disease. Nat Rev Mol Cell Biol. 2016; 18(2):127-136. DOI: 10.1038/nrm.2016.149. View

15.

Yamazaki S, Tanaka Y, Araki H, Kohda A, Sanematsu F, Arasaki T . The AP-1 transcription factor JunB is required for Th17 cell differentiation. Sci Rep. 2017; 7(1):17402. PMC: 5727176. DOI: 10.1038/s41598-017-17597-3. View

16.

Grasberger H, Gao J, Nagao-Kitamoto H, Kitamoto S, Zhang M, Kamada N . Increased Expression of DUOX2 Is an Epithelial Response to Mucosal Dysbiosis Required for Immune Homeostasis in Mouse Intestine. Gastroenterology. 2015; 149(7):1849-59. PMC: 4663159. DOI: 10.1053/j.gastro.2015.07.062. View

17.

Huang W, Littman D . Regulation of RORγt in Inflammatory Lymphoid Cell Differentiation. Cold Spring Harb Symp Quant Biol. 2016; 80:257-63. PMC: 7156073. DOI: 10.1101/sqb.2015.80.027615. View

18.

Nakano H, Piao X, Shindo R, Komazawa-Sakon S . Cellular FLICE-Inhibitory Protein Regulates Tissue Homeostasis. Curr Top Microbiol Immunol. 2015; 403:119-141. DOI: 10.1007/82_2015_448. View

19.

Wang L, Fouts D, Starkel P, Hartmann P, Chen P, Llorente C . Intestinal REG3 Lectins Protect against Alcoholic Steatohepatitis by Reducing Mucosa-Associated Microbiota and Preventing Bacterial Translocation. Cell Host Microbe. 2016; 19(2):227-39. PMC: 4786170. DOI: 10.1016/j.chom.2016.01.003. View

20.

Shindo R, Ohmuraya M, Komazawa-Sakon S, Miyake S, Deguchi Y, Yamazaki S . Necroptosis of Intestinal Epithelial Cells Induces Type 3 Innate Lymphoid Cell-Dependent Lethal Ileitis. iScience. 2019; 15:536-551. PMC: 6538961. DOI: 10.1016/j.isci.2019.05.011. View