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The Loss of Endogenous Neuregulin‐4 Increases Intestinal Epithelial Permeability and Apoptosis
Author(s) -
Bernard Jessica Kathleen,
Schumacher Michael A,
Frey Mark R
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.869.24
Subject(s) - apoptosis , intestinal permeability , inflammation , barrier function , intestinal epithelium , endocrinology , medicine , biology , immunology , microbiology and biotechnology , epithelium , pathology , biochemistry
Growth factor receptors such as the ErbB receptor tyrosine kinases can preserve intestinal barrier integrity in the face of inflammation by activating anti‐apoptotic pathways and stabilizing epithelial tight junction components. Activation of ErbB4 with pharmacological administration of its specific ligand neuregulin‐4 (NRG4) promotes epithelial cell survival by anti‐apoptotic pathways (Src and PI3K/Akt) and reduces intestinal inflammation. However, it is unclear whether ErbB4 is an essential regulator of intestinal permeability and if endogenous NRG4 is required for the response to intestinal inflammation. In this study, we investigated the role of endogenous NRG4 in intestinal barrier function in vivo . METHODS Baseline intestinal permeability in 11–17 week old wild type and NRG4 knockout mice was determined by oral gavage with FITC‐dextran (4kDa) followed by analysis of blood collected by cardiac puncture 4 h later. Barrier recovery from bacterial antigen challenge was determined 24 h after FITC‐dextran gavage and LPS‐induced injury. Ileal epithelial apoptosis was assessed by TUNEL and cleaved caspase‐3 staining of formalin‐fixed paraffin embedded tissue. RESULTS NRG4 −/− mice had compromised barrier function compared to wild type littermates at baseline, as shown by an increase in FITC‐dextran leakage to the blood (1.4‐fold increase). Furthermore, NRG4 deletion reduced the ability to recover barrier 24 hours after LPS‐induced injury (2.4‐fold increase, p <0.05). NRG4 −/− mice had exaggerated ileal epithelial cell apoptosis 24 h after LPS as well, measured by TUNEL (32 positive cells per 100 crypts (KO) vs 14.58 positive cells per 100 crypts (WT), p <0.05) and cleaved caspase‐3 staining. CONCLUSION Endogenous NRG4 promotes integrity of the intestinal epithelial barrier. Further investigation of the role of NRG4 within the intestinal mucosa may lead to more effective strategies for targeting barrier dysfunction seen in diseases such as inflammatory bowel disease or necrotizing enterocolitis. Support or Funding Information Supported by NIH award DK095004 and a Senior Research Award from The Crohn's and Colitis Foundation. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .