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LRIG1 inhibits STAT3-dependent inflammation to maintain corneal homeostasis
Takahiro Nakamura, … , Yann Barrandon, Shigeru Kinoshita
Takahiro Nakamura, … , Yann Barrandon, Shigeru Kinoshita
Published December 9, 2013
Citation Information: J Clin Invest. 2014;124(1):385-397. https://doi.org/10.1172/JCI71488.
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Research Article Article has an altmetric score of 15

LRIG1 inhibits STAT3-dependent inflammation to maintain corneal homeostasis

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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 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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Figure 6

Stat3 activation induced by the loss of Lrig1.

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Stat3 activation induced by the loss of Lrig1.
 
(A) Relative expressio...
(A) Relative expression of Stat3 in Lrig1 WT and Lrig1-KO corneas (n = 4 corneas mixed, 3 months). (B) Stat3 expression transcriptionally inhibited by Lrig1. Luciferase reporter assay using mouse cultured conjunctival fibroblast and keratinocytes, with or without IL-6 stimulation. *P < 0.01 (n = 4). (C) Immunohistochemistry for Stat3 and pStat3 (green) in Lrig1 WT and Lrig1-KO corneas (3 months), with or without wound. Nuclei are counterstained with PI (red). Dashed lines indicate the border between epithelium and underlying stroma. Scale bar: 100 μm. (D) Relative expression of JAK/STAT-related molecules (gp130, SOCS3, and JAK1 and JAK2) in Lrig1 WT and Lrig1-KO corneas, with or without wound (n = 4 corneas mixed, 3 months).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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