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LRIG1 inhibits STAT3-dependent inflammation to maintain corneal homeostasis

Research output: Contribution to journalJournal article

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  • Takahiro Nakamura
  • Junji Hamuro
  • Mikiro Takaishi
  • Szandor Simmons
  • Kazuichi Maruyama
  • Andrea Zaffalon
  • Adam J. Bentley
  • Satoshi Kawasaki
  • Maho Nagata-Takaoka
  • Nigel J. Fullwood
  • Satoshi Itami
  • Shigetoshi Sano
  • Masaru Ishii
  • Yann Barrandon
  • Shigeru Kinoshita
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<mark>Journal publication date</mark>2/01/2014
<mark>Journal</mark>Journal of Clinical Investigation
Issue number1
Volume124
Number of pages13
Pages (from-to)385-397
Publication StatusPublished
<mark>Original language</mark>English

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.