title: TGF-β1 improves mucosal IgA dysfunction and dysbiosis following intestinal ischaemia-reperfusion in mice.
abstract: Intestinal ischaemia/reperfusion (I/R) severely disrupts gut barriers and leads to high mortality in the critical care setting. Transforming growth factor (TGF)-β1 plays a pivotal role in intestinal cellular and immune regulation. However, the effects of TGF-β1 on intestinal I/R injury remain unclear. Thus, we aimed to investigate the effects of TGF-β1 on gut barriers after intestinal I/R and the molecular mechanisms. Intestinal I/R model was produced in mice by clamping the superior mesenteric artery for 1 hr followed by reperfusion. Recombinant TGF-β1 was intravenously infused at 15 min. before ischaemia. The results showed that within 2 hrs after reperfusion, intestinal I/R disturbed intestinal immunoglobulin A class switch recombination (IgA CSR), the key process of mucosal IgA synthesis, and resulted in IgA dysfunction, as evidenced by decreased production and bacteria-binding capacity of IgA. Meanwhile, the disruptions of intestinal microflora and mucosal structure were exhibited. Transforming growth factor-β1 activated IgA CSR as evidenced by the increased activation molecules and IgA precursors. Strikingly, TGF-β1 improved intestinal mucosal IgA dysfunction, dysbiosis and epithelial damage at the early stage after reperfusion. In addition, SB-431542, a specific inhibitor of activating mothers against decapentaplegic homologue (SMAD) 2/3, totally blocked the inductive effect of TGF-β1 on IgA CSR and almost abrogated the above protective effects on intestinal barriers. Taken together, our study demonstrates that TGF-β1 protects intestinal mucosal IgA immunity, microbiota and epithelial integrity against I/R injury mainly through TGF-β receptor 1/SMAD 2/3 pathway. Induction of IgA CSR may be involved in the protection conferred by TGF-β1.
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xu-Yu
authors.initials: XY
authors.lastname: Zhang
authors.affiliation: Surgical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Zi-Meng
authors.initials: ZM
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Hu-Fei
authors.initials: HF
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yun-Sheng
authors.initials: YS
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Shi-Hong
authors.initials: SH
authors.lastname: Wen
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jian-Tong
authors.initials: JT
authors.lastname: Shen
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Wen-Qi
authors.initials: WQ
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Ke-Xuan
authors.initials: KX
authors.lastname: Liu
mesh_terms: D000818:Animals; D001419:Bacteria / Q000378:metabolism; D064806:Dysbiosis / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism*; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007413:Intestinal Mucosa / Q000098:blood supply* / Q000503:physiopathology*; D008297:Male; D008807:Mice, Inbred BALB C; D011995:Recombination, Genetic / Q000235:genetics; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy*; D016019:Survival Analysis; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D007070:Immunoglobulin A; D053773:Transforming Growth Factor beta1
keywords: class switching; immunoglobulin A; ischemia-reperfusion injury; microbiota; mucosal immunity
references.citation: Crit Care Med. 2008 May;36(5):1564-72
references.pmid: 18434898
references.citation: Anesthesiology. 2012 May;116(5):1035-46
references.pmid: 22417965
references.citation: Science. 2012 Apr 27;336(6080):485-9
references.pmid: 22539724
references.citation: J Immunol. 2004 May 15;172(10):6259-64
references.pmid: 15128814
references.citation: MBio. 2014 Sep 23;5(5):e01361-14
references.pmid: 25249279
references.citation: EMBO Rep. 2006 Jul;7(7):688-93
references.pmid: 16819463
references.citation: World J Gastroenterol. 2014 Dec 7;20(45):16795-810
references.pmid: 25492994
references.citation: Intensive Care Med. 2015 Apr;41(4):667-76
references.pmid: 25731634
references.citation: Mol Pharmacol. 2002 Jul;62(1):65-74
references.pmid: 12065756
references.citation: World J Gastroenterol. 2008 May 14;14(18):2894-9
references.pmid: 18473417
references.citation: Nat Rev Immunol. 2013 May;13(5):321-35
references.pmid: 23618829
references.citation: Anesth Analg. 2008 Dec;107(6):1884-91
references.pmid: 19020134
references.citation: J Leukoc Biol. 2009 May;85(5):744-50
references.pmid: 19168593
references.citation: Surgeon. 2012 Dec;10(6):350-6
references.pmid: 22534256
references.citation: Dig Dis Sci. 2011 Apr;56(4):1171-7
references.pmid: 20931284
references.citation: Gut. 1999 Aug;45(2):223-8
references.pmid: 10403734
references.citation: Am J Physiol Gastrointest Liver Physiol. 2011 Dec;301(6):G1020-30
references.pmid: 21903760
references.citation: Ann Surg. 2012 Mar;255(3):492-503
references.pmid: 22266638
references.citation: Crit Care Med. 2006 Jan;34(1):182-7
references.pmid: 16374173
references.citation: Antimicrob Agents Chemother. 2009 Nov;53(11):4694-701
references.pmid: 19738024
references.citation: Trends Mol Med. 2014 Apr;20(4):214-23
references.pmid: 24055446
references.citation: Dig Dis Sci. 2011 Aug;56(8):2361-5
references.pmid: 21384123
references.citation: Annu Rev Immunol. 2010;28:243-73
references.pmid: 20192805
references.citation: Dig Dis Sci. 2013 May;58(5):1207-17
references.pmid: 23306843
references.citation: Cell Host Microbe. 2007 Nov 15;2(5):328-39
references.pmid: 18005754
references.citation: J Virol. 2012 Oct;86(20):10924-34
references.pmid: 22896605
references.citation: J Immunol. 2001 Oct 1;167(7):3677-81
references.pmid: 11564781
references.citation: Curr Opin Gastroenterol. 2000 Nov;16(6):541-5
references.pmid: 17031135
references.citation: Respirology. 2009 Nov;14(8):1173-9
references.pmid: 19909463
references.citation: J Immunol. 2009 Feb 15;182(4):1854-9
references.pmid: 19201837
references.citation: Nat Rev Microbiol. 2010 Sep;8(9):656-67
references.pmid: 20694027
references.citation: Brain Behav Immun. 2012 Nov;26(8):1300-9
references.pmid: 22884415
references.citation: BMC Neurosci. 2008 Dec 10;9:117
references.pmid: 19077183
references.citation: Dig Dis Sci. 2015 Sep;60(9):2662-9
references.pmid: 25944714
references.citation: PLoS One. 2012;7(7):e42027
references.pmid: 22848694
references.citation: Endokrynol Pol. 2013;64(5):384-96
references.pmid: 24186596
references.citation: Nat Rev Immunol. 2012 Dec;12(12):821-32
references.pmid: 23103985
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):1981-6
references.pmid: 14766966
references.citation: Immunity. 2008 Jun;28(6):740-50
references.pmid: 18549797
references.citation: Curr Pharm Des. 2009;15(13):1537-45
references.pmid: 19442171
references.citation: Infect Immun. 2013 Aug;81(8):3027-34
references.pmid: 23753631
references.citation: Nature. 2001 Oct 11;413(6856):639-43
references.pmid: 11675788
references.citation: Dig Dis Sci. 2004 Sep;49(9):1359-77
references.pmid: 15481305
references.citation: Cell. 2014 Aug 28;158(5):1000-10
references.pmid: 25171403
references.citation: J Immunol. 2009 Jan 1;182(1):5-7
references.pmid: 19109126