LRIG1 inhibits STAT3-dependent inflammation to maintain corneal homeostasis
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
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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Research Article

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 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 7

Reproduction of pathological phenotypes evident in Lrig1-KO corneas resulting from the activation of Stat3.

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Reproduction of pathological phenotypes evident in Lrig1-KO corneas resu...
(A and B) Slit-lamp photographs and histological appearances with H&E staining of control and K5 Stat3 Tg mouse corneas (6 months). Scale bars: 100 μm. (C) Immunohistochemistry for keratin 12, loricrin, F4/80, and CD3 (green) in control and K5 Stat3 Tg corneas. Nuclei are counterstained with PI (red). Scale bar: 100 μm. Generation of Lrig1-KO corneal phenotypes rescued by blocking Stat3. (D) Seven days after the first corneal wound (7 d), Lrig1 WT and Lrig1-KO corneas (3 months) treated with STA21 were transparent, without inflammation, yet Lrig1-KO corneas without STA21 showed corneal opacity (arrow). (E) Seven days after the second wound (14 d), Lrig1 WT corneas without STA21 still maintained their transparency, while Lrig1-KO corneas without STA21 exhibited corneal plaques with inflammation (arrows). (F) Histological appearances of the resultant corneas (14 d) with H&E staining. Scale bar: 100 μm.