{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:43:42Z","timestamp":1777337022686,"version":"3.51.4"},"reference-count":48,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T00:00:00Z","timestamp":1692316800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Boston Keratoprosthesis Fund, Mass Eye and Ear","award":["5P30EY003790"],"award-info":[{"award-number":["5P30EY003790"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Limbal stem cell (LSC) deficiency is a frequent and severe complication after chemical injury to the eye. Previous studies have assumed this is mediated directly by the caustic agent. Here we show that LSC damage occurs through immune cell mediators, even without direct injury to LSCs. In particular, pH elevation in the anterior chamber (AC) causes acute uveal stress, the release of inflammatory cytokines at the basal limbal tissue, and subsequent LSC damage and death. Peripheral C-C chemokine receptor type 2 positive\/CX3C motif chemokine receptor 1 negative (CCR2+ CX3CR1\u2212) monocytes are the key mediators of LSC damage through the upregulation of tumor necrosis factor-alpha (TNF-\u03b1) at the limbus. In contrast to peripherally derived monocytes, CX3CR1+ CCR2\u2212 tissue-resident macrophages have a protective role, and their depletion prior to injury exacerbates LSC loss and increases LSC vulnerability to TNF-\u03b1-mediated apoptosis independently of CCR2+ cell infiltration into the tissue. Consistently, repopulation of the tissue by new resident macrophages not only restores the protective M2-like phenotype of macrophages but also suppresses LSC loss after exposure to inflammatory signals. These findings may have clinical implications in patients with LSC loss after chemical burns or due to other inflammatory conditions.<\/jats:p>","DOI":"10.3390\/cells12162089","type":"journal-article","created":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T10:14:38Z","timestamp":1692353678000},"page":"2089","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Opposing Roles of Blood-Borne Monocytes and Tissue-Resident Macrophages in Limbal Stem Cell Damage after Ocular Injury"],"prefix":"10.3390","volume":"12","author":[{"given":"Chengxin","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Massachusetts Eye and Ear and Schepens Eye Research Institute, Mass General Brigham, Harvard Medical School, Boston, MA 02114, USA"},{"name":"Boston Keratoprosthesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear, Mass General Brigham, Harvard Medical School, Boston, MA 02114, USA"},{"name":"Disruptive Technology Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9169-8314","authenticated-orcid":false,"given":"Fengyang","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Massachusetts Eye and Ear and Schepens Eye Research Institute, Mass General Brigham, Harvard Medical School, Boston, MA 02114, USA"},{"name":"Boston Keratoprosthesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear, Mass General Brigham, Harvard Medical School, Boston, MA 02114, USA"},{"name":"Disruptive Technology Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mirja","family":"Mittermaier","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Massachusetts Eye and Ear and Schepens Eye Research Institute, Mass General Brigham, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce","family":"Ksander","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Massachusetts Eye and Ear and Schepens Eye Research Institute, Mass General Brigham, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5732-5100","authenticated-orcid":false,"given":"Reza","family":"Dana","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Massachusetts Eye and Ear and Schepens Eye Research Institute, Mass General Brigham, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claes H.","family":"Dohlman","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Massachusetts Eye and Ear and Schepens Eye Research Institute, Mass General Brigham, Harvard Medical School, Boston, MA 02114, USA"},{"name":"Boston Keratoprosthesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear, Mass General Brigham, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8622-6478","authenticated-orcid":false,"given":"Demetrios G.","family":"Vavvas","sequence":"additional","affiliation":[{"name":"Retina Service, Department of Ophthalmology, Massachusetts Eye and Ear, Mass General Brigham, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Chodosh","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Massachusetts Eye and Ear and Schepens Eye Research Institute, Mass General Brigham, Harvard Medical School, Boston, MA 02114, USA"},{"name":"Boston Keratoprosthesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear, Mass General Brigham, Harvard Medical School, Boston, MA 02114, USA"},{"name":"Disruptive Technology Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA"},{"name":"Department of Ophthalmology and Visual Sciences, University of New Mexico School of Medicine, Albuquerque, NM 87108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4544-4452","authenticated-orcid":false,"given":"Eleftherios I.","family":"Paschalis","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Massachusetts Eye and Ear and Schepens Eye Research Institute, Mass General Brigham, Harvard Medical School, Boston, MA 02114, USA"},{"name":"Boston Keratoprosthesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear, Mass General Brigham, Harvard Medical School, Boston, MA 02114, USA"},{"name":"Disruptive Technology Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1097\/ICO.0b013e3182012a4f","article-title":"Chemical burns to the eye: Paradigm shifts in treatment","volume":"30","author":"Dohlman","year":"2011","journal-title":"Cornea"},{"key":"ref_2","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1136\/bjo.78.5.401","article-title":"Corneal epithelial wound healing","volume":"78","author":"Dua","year":"1994","journal-title":"Br. 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Md. 1950)"},{"key":"ref_15","doi-asserted-by":"publisher","first-page":"2056","DOI":"10.1016\/j.ajpath.2020.07.006","article-title":"Glaucoma after ocular surgery or trauma: The role of infiltrating monocytes and their response to cytokine inhibitors","volume":"190","author":"Chen","year":"2020","journal-title":"Am. J. Pathol."},{"key":"ref_16","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. 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