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.

Ocular surface reconstruction using stem cell and tissue engineering

“…Many putative corneal epithelial stem cell markers (e.g. p63, ABCG2, Integrin a9, Keratin 15, N-cadherin, NGF/TrkA, Integrin a6/CD71, Hes1, p75, Nectin 3, Importin 13, Nucleostemin, CD38/157, Lrig1, ABCB5, WNT7A) have been reported worldwide (Di Girolamo et al, 2008;Hayashi et al, 2008Hayashi et al, , 2007Horenstein et al, 2009;Kawashima et al, 2009;Ksander et al, 2014;Kusanagi et al, 2009;Nakamura et al, 2014Nakamura et al, , 2008aOuyang et al, 2014;Pajoohesh-Ganji et al, 2006;Pellegrini et al, 2001;Qi et al, 2008;Wang et al, 2009;Watanabe et al, 2004;Yoshida et al, 2006) (Fig. 10).…”

Lrig1 and CD44v3 Expression in the Human Folliculosebaceous Unit

“…We next studied the expression of EGFR and CD44v3 in these clusters, since CD44v3 has been shown to modulate EGFR signaling [6,7,8]. Two human skin serial sections from the scalp and from the retroauricular area were stained with antibodies directed against the human form of Lrig1 [1,9,10], EGFR (Cell Signaling, #4267, Danvers, Mass., USA) and CD44v3 (BMS144, Bender MedSystems, Vienna, Austria). The previously described clusters of Lrig1+ cells in the IFE were detected in the basal layer, and these clusters were negative for EGFR (fig.…”

LRIG1 Extracellular Domain: Structure and Function Analysis

“…It contains 19 β-strands with 16 LRRs (numbered [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. There are 15 complete LRRs [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15], each with 23-27 residues, where 11 LRRs have the 24-residue repeat [LxxLxLxxNxLxxLxxxx(Hφ)xx(Hφ)xx, where Hφ is any hydrophobic amino acid residue]. LRR16 is only a partial repeat with a new pattern LxxLxIxSxxFx, where Ser appears to replace Asn in the consensus repeat (LxxLxLxxNxLxx).…”

“…In the last decade, LRIG1 has been reported to interact with many receptor tyrosine kinases, GDNF/c-Ret [11], E-cadherin [12], JAK/STAT [13], c-Met [14,15], and the EGFR family [7,9] signalling systems. In some cases, LRIG1 is reported to reduce receptor levels by increasing the rates of degradation [7]; in other reports, LRIG1 appears to bind directly to the receptor kinase (e.g., the EGFR) [9].…”