{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T06:45:28Z","timestamp":1784616328739,"version":"3.55.0"},"reference-count":33,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2018,10,16]],"date-time":"2018-10-16T00:00:00Z","timestamp":1539648000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["EY6177"],"award-info":[{"award-number":["EY6177"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Thrombospondin-1-deficient (TSP-1\u2212\/\u2212) mice are used as an animal model of Sj\u00f6gren\u2019s Syndrome because they exhibit many of the symptoms associated with the autoimmune type of dry eye found in primary Sj\u00f6gren\u2019s Syndrome. This type of dry eye is linked to the inflammation of the lacrimal gland, conjunctiva, and cornea, and is thought to involve dysfunction of the complex neuronal reflex arc that mediates tear production in response to noxious stimuli on the ocular surface. This study characterizes the structural and functional changes to the corneal nerves that are the afferent arm of this arc in young and older TSP-1\u2212\/\u2212 and wild type (WT) mice. The structure and subtype of nerves were characterized by immunohistochemistry, in vivo confocal microscopy, and confocal microscopy. Cytokine expression analysis was determined by Q-PCR and the number of monocytes was measured by immunohistochemistry. We found that only the pro-inflammatory cytokine MIP-2 increased in young corneas of TSP-1\u2212\/\u2212 compared to WT mice, but tumor necrosis factor-\u03b1 (TNF-\u03b1), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2) all increased in older TSP-1\u2212\/\u2212 mouse corneas. In contrast, CD11b+ pro-inflammatory monocytes did not increase even in older mouse corneas. Calcitonin gene-related peptide (CGRP)-, but not Substance P (SubP)-containing corneal nerves decreased in older, but not younger TSP-1\u2212\/\u2212 compared to WT mouse corneas. We conclude that CGRP-containing corneal sensory nerves exhibit distinct structural deficiencies as disease progresses in TSP-1\u2212\/\u2212 mice, suggesting that: (1) TSP-1 is needed for the development or repair of these nerves and (2) impaired afferent corneal nerve structure and hence function may contribute to ocular surface dysfunction that develops as TSP-1\u2212\/\u2212 mice age.<\/jats:p>","DOI":"10.3390\/ijms19103191","type":"journal-article","created":{"date-parts":[[2018,10,16]],"date-time":"2018-10-16T11:07:51Z","timestamp":1539688071000},"page":"3191","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Thrombospondin-1 Is Necessary for the Development and Repair of Corneal Nerves"],"prefix":"10.3390","volume":"19","author":[{"given":"Yukako","family":"Tatematsu","sequence":"first","affiliation":[{"name":"Schepens Eye Research Institute\/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qalbi","family":"Khan","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute\/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA"},{"name":"Department of Medical Biology, Faculty of Health Sciences, University of Troms\u00f8, Troms\u00f8 9037, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Blanco","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute\/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Bair","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute\/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin R.","family":"Hodges","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute\/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharmila","family":"Masli","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Boston University School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darlene A.","family":"Dartt","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute\/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.jtos.2017.05.008","article-title":"TFOS DEWS II Definition and Classification Report","volume":"15","author":"Craig","year":"2017","journal-title":"Ocul. 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