PMID- 30171165 OWN - NLM STAT- MEDLINE DCOM- 20190722 LR - 20191023 IS - 1550-6606 (Electronic) IS - 0022-1767 (Print) IS - 0022-1767 (Linking) VI - 201 IP - 8 DP - 2018 Oct 15 TI - Neutrophils Promote Amphiregulin Production in Intestinal Epithelial Cells through TGF-beta and Contribute to Intestinal Homeostasis. PG - 2492-2501 LID - 10.4049/jimmunol.1800003 [doi] AB - Neutrophils are the first responders to sites of inflammation when the intestinal epithelial barrier is breached and the gut microbiota invade. Despite current efforts in understanding the role of neutrophils in intestinal homeostasis, the complex interactions between neutrophils and intestinal epithelial cells (IECs) is still not well characterized. In this study, we demonstrated that neutrophils enhanced production of amphiregulin (AREG), a member of the EGFR ligand family, by IECs, which promoted IEC barrier function and tissue repair. Depletion of neutrophils resulted in more severe colitis in mice because of decreased AREG production by IECs upon dextran sodium sulfate (DSS) insult. Administration of AREG restored epithelial barrier function and ameliorated colitis. Furthermore, neutrophil-derived TGF-beta promoted AREG production by IECs. Mechanistically, TGF-beta activated MEK1/2 signaling, and inhibition of MEK1/2 abrogated TGF-beta-induced AREG production by IECs. Collectively, these findings reveal that neutrophils play an important role in the maintenance of IEC barrier function and homeostasis. CI - Copyright (c) 2018 by The American Association of Immunologists, Inc. FAU - Chen, Feidi AU - Chen F AD - Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555. FAU - Yang, Wenjing AU - Yang W AD - Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555. AD - Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China. FAU - Huang, Xiangsheng AU - Huang X AD - Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555. FAU - Cao, Anthony T AU - Cao AT AD - Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555. FAU - Bilotta, Anthony J AU - Bilotta AJ AD - Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555. AD - Department of Medicine, University of Texas Medical Branch, Galveston, TX 77555; and. FAU - Xiao, Yi AU - Xiao Y AD - Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555. FAU - Sun, Mingming AU - Sun M AD - Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555. AD - Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China. FAU - Chen, Liang AU - Chen L AD - Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555. AD - Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China. FAU - Ma, Chunyan AU - Ma C AD - Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555. FAU - Liu, Xiuping AU - Liu X AUID- ORCID: 0000-0003-4832-4322 AD - Department of Experimental Therapeutics, MD Anderson Cancer Center, University of Texas, Houston, TX 77230. FAU - Liu, Chang-Gong AU - Liu CG AD - Department of Experimental Therapeutics, MD Anderson Cancer Center, University of Texas, Houston, TX 77230. FAU - Yao, Suxia AU - Yao S AD - Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555. FAU - Dann, Sara M AU - Dann SM AD - Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555. AD - Department of Medicine, University of Texas Medical Branch, Galveston, TX 77555; and. FAU - Liu, Zhanju AU - Liu Z AUID- ORCID: 0000-0002-0326-543X AD - Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China. FAU - Cong, Yingzi AU - Cong Y AUID- ORCID: 0000-0003-4167-7395 AD - Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555; yicong@utmb.edu. AD - Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555. LA - eng GR - R01 DK079918/DK/NIDDK NIH HHS/United States GR - R01 DK098370/DK/NIDDK NIH HHS/United States GR - R01 DK105585/DK/NIDDK NIH HHS/United States GR - R01 DK112436/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180831 PL - United States TA - J Immunol JT - Journal of immunology (Baltimore, Md. : 1950) JID - 2985117R RN - 0 (Amphiregulin) RN - 0 (Transforming Growth Factor beta) RN - 9042-14-2 (Dextran Sulfate) RN - EC 2.7.12.2 (MAP Kinase Kinase 1) SB - IM MH - Amphiregulin/*metabolism MH - Animals MH - Cells, Cultured MH - Colitis/chemically induced/*immunology MH - Dextran Sulfate MH - Disease Models, Animal MH - Female MH - Homeostasis MH - Humans MH - Inflammatory Bowel Diseases/*immunology MH - Intestinal Mucosa/*physiology MH - MAP Kinase Kinase 1/metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Neutrophils/*physiology MH - Signal Transduction MH - Transforming Growth Factor beta/*metabolism PMC - PMC6179911 MID - NIHMS1503856 COIS- Disclosures: The authors report no financial conflict of interests. EDAT- 2018/09/02 06:00 MHDA- 2019/07/23 06:00 PMCR- 2019/10/15 CRDT- 2018/09/02 06:00 PHST- 2018/01/03 00:00 [received] PHST- 2018/08/09 00:00 [accepted] PHST- 2018/09/02 06:00 [pubmed] PHST- 2019/07/23 06:00 [medline] PHST- 2018/09/02 06:00 [entrez] PHST- 2019/10/15 00:00 [pmc-release] AID - jimmunol.1800003 [pii] AID - 10.4049/jimmunol.1800003 [doi] PST - ppublish SO - J Immunol. 2018 Oct 15;201(8):2492-2501. doi: 10.4049/jimmunol.1800003. Epub 2018 Aug 31.