title: MyD88 adaptor-like (Mal) functions in the epithelial barrier and contributes to intestinal integrity via protein kinase C.
abstract: MyD88 adapter-like (Mal)-deficient mice displayed increased susceptibility to oral but not intraperitoneal infection with Salmonella Typhimurium. Bone marrow chimeras demonstrated that mice with Mal-deficient non-hematopoietic cells were more susceptible to infection, indicating a role for Mal in non-myeloid cells. We observed perturbed barrier function in Mal(-/-) mice, as indicated by reduced electrical resistance and increased mucosa blood permeability following infection. Altered expression of occludin, Zonula occludens-1, and claudin-3 in intestinal epithelia from Mal(-/-) mice suggest that Mal regulates tight junction formation, which may in part contribute to intestinal integrity. Mal interacted with several protein kinase C (PKC) isoforms in a Caco-2 model of intestinal epithelia and inhibition of Mal or PKC increased permeability and bacterial invasion via a paracellular route, while a pan-PKC inhibitor increased susceptibility to oral infection in mice. Mal signaling is therefore beneficial to the integrity of the intestinal barrier during infection.
authors.affiliation: Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
authors.forename: S C
authors.initials: SC
authors.lastname: Corr
authors.affiliation: Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
authors.forename: E M
authors.initials: EM
authors.lastname: Palsson-McDermott
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, CA, US.
authors.forename: I
authors.initials: I
authors.lastname: Grishina
authors.affiliation: Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: S P
authors.initials: SP
authors.lastname: Barry
authors.affiliation: Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: G
authors.initials: G
authors.lastname: Aviello
authors.affiliation: Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
authors.forename: N J
authors.initials: NJ
authors.lastname: Bernard
authors.affiliation: Alimentary Pharmabiotic Centre, Department of Microbiology, University College Cork, Cork, Ireland.
authors.forename: P G
authors.initials: PG
authors.lastname: Casey
authors.affiliation: Molecular Medicine Laboratories, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
authors.forename: J B J
authors.initials: JB
authors.lastname: Ward
authors.affiliation: Molecular Medicine Laboratories, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
authors.forename: S J
authors.initials: SJ
authors.lastname: Keely
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, CA, US.
authors.forename: S
authors.initials: S
authors.lastname: Dandekar
authors.affiliation: 1] Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland [2] Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin, Dublin, Ireland [3] National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland [4] These authors contributed equally to this work.
authors.forename: P G
authors.initials: PG
authors.lastname: Fallon
authors.affiliation: 1] Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland [2] These authors contributed equally to this work.
authors.forename: L A J
authors.initials: LA
authors.lastname: O'Neill
mesh_terms: D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D007422:Intestines / Q000276:immunology / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism*; D021381:Protein Transport; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012480:Salmonella Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D012486:Salmonella typhimurium / Q000276:immunology; D015398:Signal Transduction; D062725:Tight Junction Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; C499045:TIRAP protein, mouse; D062725:Tight Junction Proteins; D011493:Protein Kinase C