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The loss of endogenous Neuregulin‐4 impairs intestinal epithelial recovery from LPS‐induced injury.
Author(s) -
Bernard Jessica Kathleen,
Schumacher Michael,
Katada Kay,
Fernandez Esteban,
Frey Mark
Publication year - 2020
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.2020.34.s1.06745
Subject(s) - inflammation , apoptosis , intestinal permeability , protein kinase b , endogeny , proinflammatory cytokine , tumor necrosis factor alpha , lipopolysaccharide , medicine , cytokine , neuregulin 1 , endocrinology , biology , signal transduction , immunology , microbiology and biotechnology , biochemistry
Growth factor receptors such as EGFR/erbB family members can preserve intestinal integrity by the activation of anti‐apoptotic pathways and stabilization of epithelial tight junction components. Previously we have shown that the activation of ErbB4 by its specific ligand Neuregulin‐4 (NRG4) promotes epithelial cell survival through Src and PI3 kinase/AKT pathways and reduces intestinal inflammation. However, it is unclear whether ErbB4 is an essential regulator of the intestinal barrier and if endogenous NRG4 is required for the response to intestinal inflammation. In this study we investigated the role of endogenous NRG4 as it pertains to intestinal barrier function and cell survival in vivo . METHODS NRG4 knockout mice and wild type littermates were challenged with lipopolysaccharide (LPS) injection. Intestinal permeability was determined by gavaging with 4‐kDa FITC‐dextran and collecting blood for fluorescence analysis after 4 or 24 h. The relative mRNA level of inflammatory cytokines was determined by taqman gene assays using full thickness ileal homogenates. Fixed ileal tissue for analysis of apoptosis was assessed by TUNEL and cleaved caspase‐3 staining, proliferation was evaluated by KI67 staining, and tight junction localization was determined by ZO‐1 staining. RESULTS The loss of endogenous NRG4 in unchallenged mice did not alter baseline intestinal permeability, apoptosis, or proliferation. Interestingly, baseline inflammatory cytokine levels were reduced in the NRG4‐null mice compared to WT littermates. NRG4 KO mice showed significantly increased permeability to 4‐kDa FITC‐dextran (P<0.05) and enterocyte apoptosis (P<0.05) 24 hours after LPS‐induced injury, which was not seen 4 hours after LPS challenge. Furthermore, ZO‐1 redistribution was apparent within the base of the crypt 24 hours after LPS challenge in the NRG4 KO mice, while redistribution was only visible after 4 hours in WT mice. CONCLUSION The loss of endogenous NRG4 impairs the recovery of intestinal epithelial barrier after LPS‐induced injury. Further investigation of this recovery mechanism may reveal more effective strategies for targeting epithelial barrier dysfunction seen in intestinal diseases such as inflammatory bowel disease. Support or Funding Information 2 R01 DK095004 06A1