title: LRIG1 inhibits STAT3-dependent inflammation to maintain corneal homeostasis.
abstract: Corneal integrity and transparency are indispensable for good vision. Cornea homeostasis is entirely dependent upon corneal stem cells, which are required for complex wound-healing processes that restore corneal integrity following epithelial damage. Here, we found that leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is highly expressed in the human holoclone-type corneal epithelial stem cell population and sporadically expressed in the basal cells of ocular-surface epithelium. In murine models, LRIG1 regulated corneal epithelial cell fate during wound repair. Deletion of Lrig1 resulted in impaired stem cell recruitment following injury and promoted a cell-fate switch from transparent epithelium to keratinized skin-like epidermis, which led to corneal blindness. In addition, we determined that LRIG1 is a negative regulator of the STAT3-dependent inflammatory pathway. Inhibition of STAT3 in corneas of Lrig1-/- mice rescued pathological phenotypes and prevented corneal opacity. Additionally, transgenic mice that expressed a constitutively active form of STAT3 in the corneal epithelium had abnormal features, including corneal plaques and neovascularization similar to that found in Lrig1-/- mice. Bone marrow chimera experiments indicated that LRIG1 also coordinates the function of bone marrow-derived inflammatory cells. Together, our data indicate that LRIG1 orchestrates corneal-tissue transparency and cell fate during repair, and identify LRIG1 as a key regulator of tissue homeostasis.
authors: Takahiro
authors: T
authors: Nakamura
authors: Junji
authors: J
authors: Hamuro
authors: Mikiro
authors: M
authors: Takaishi
authors: Szandor
authors: S
authors: Simmons
authors: Kazuichi
authors: K
authors: Maruyama
authors: Andrea
authors: A
authors: Zaffalon
authors: Adam J
authors: AJ
authors: Bentley
authors: Satoshi
authors: S
authors: Kawasaki
authors: Maho
authors: M
authors: Nagata-Takaoka
authors: Nigel J
authors: NJ
authors: Fullwood
authors: Satoshi
authors: S
authors: Itami
authors: Shigetoshi
authors: S
authors: Sano
authors: Masaru
authors: M
authors: Ishii
authors: Yann
authors: Y
authors: Barrandon
authors: Shigeru
authors: S
authors: Kinoshita
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D003228:Conjunctiva / Q000473:pathology; D003315:Cornea / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019573:Epithelium, Corneal / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D007634:Keratitis / Q000276:immunology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D059467:Transcriptome; D014945:Wound Healing
chemical_list: C101671:Lrig1 protein, mouse; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse