title: Sterile Inflammation Enhances ECM Degradation in Integrin β1 KO Embryonic Skin.
abstract: Epidermal knockout of integrin β1 results in complete disorganization of the basement membrane (BM), resulting in neonatal lethality. Here, we report that this disorganization is exacerbated by an early embryonic inflammatory response involving the recruitment of tissue-resident and monocyte-derived macrophages to the dermal-epidermal junction, associated with increased matrix metalloproteinase activity. Remarkably, the skin barrier in the integrin β1 knockout animals is intact, suggesting that this inflammatory response is initiated in a sterile environment. We demonstrate that the molecular mechanism involves de novo expression of integrin αvβ6 in the basal epidermal cells, which activates a TGF-β1 driven inflammatory cascade resulting in upregulation of dermal NF-κB in a Tenascin C-dependent manner. Importantly, treatment of β1 KO embryos in utero with small molecule inhibitors of TGF-βR1 and NF-κB results in marked rescue of the BM defects and amelioration of immune response, revealing an unconventional immuno-protective role for integrin β1 during BM remodeling.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK PO, Bellary Road, Bangalore 560065, India; SASTRA University, Thirumalaisamudram, Thanjavur, Tamil Nadu 613401, India.
authors.forename: Ambika S
authors.initials: AS
authors.lastname: Kurbet
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK PO, Bellary Road, Bangalore 560065, India; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Samarth
authors.initials: S
authors.lastname: Hegde
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK PO, Bellary Road, Bangalore 560065, India; SASTRA University, Thirumalaisamudram, Thanjavur, Tamil Nadu 613401, India.
authors.forename: Oindrila
authors.initials: O
authors.lastname: Bhattacharjee
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK PO, Bellary Road, Bangalore 560065, India.
authors.forename: Srujan
authors.initials: S
authors.lastname: Marepally
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK PO, Bellary Road, Bangalore 560065, India.
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Vemula
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK PO, Bellary Road, Bangalore 560065, India; Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. Electronic address: srikala@instem.res.in.
authors.forename: Srikala
authors.initials: S
authors.lastname: Raghavan
mesh_terms: D000818:Animals; D005109:Extracellular Matrix / Q000473:pathology*; D007249:Inflammation / Q000276:immunology*; D019012:Integrin beta1 / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology; D012867:Skin / Q000196:embryology* / Q000276:immunology*
chemical_list: D019012:Integrin beta1