Final published version, 8.4 MB, PDF document
Final published version
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - LRIG1 inhibits STAT3-dependent inflammation to maintain corneal homeostasis
AU - Nakamura, Takahiro
AU - Hamuro, Junji
AU - Takaishi, Mikiro
AU - Simmons, Szandor
AU - Maruyama, Kazuichi
AU - Zaffalon, Andrea
AU - Bentley, Adam J.
AU - Kawasaki, Satoshi
AU - Nagata-Takaoka, Maho
AU - Fullwood, Nigel J.
AU - Itami, Satoshi
AU - Sano, Shigetoshi
AU - Ishii, Masaru
AU - Barrandon, Yann
AU - Kinoshita, Shigeru
PY - 2014/1/2
Y1 - 2014/1/2
N2 - 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.
AB - 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.
KW - Animals
KW - Bone Marrow Transplantation
KW - Cells, Cultured
KW - Conjunctiva
KW - Cornea
KW - Epithelium, Corneal
KW - Humans
KW - Keratinocytes
KW - Keratitis
KW - Membrane Glycoproteins
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Nerve Tissue Proteins
KW - STAT3 Transcription Factor
KW - Stem Cells
KW - Transcriptome
KW - Wound Healing
U2 - 10.1172/JCI71488
DO - 10.1172/JCI71488
M3 - Journal article
C2 - 24316976
VL - 124
SP - 385
EP - 397
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 1
ER -