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Activity of cathepsin S (CTSS), a cysteine protease, is significantly and specifically increased in SS patient tears. The soluble chemokine, CX3CL1 (fractalkine), is cleaved from membrane-bound CX3CL1 by proteases including CTSS. We show that CX3CL1 is significantly elevated by 2.5-fold in tears (p\u2009=\u20090.0116) and 1.4-fold in LG acinar cells (LGAC)(p\u2009=\u20090.0026) from male NOD mice, a model of autoimmune dacryoadenitis in SS, relative to BALB\/c controls. Primary mouse LGAC and human corneal epithelial cells (HCE-T cells) exposed to interferon-gamma, a cytokine elevated in SS, showed up to 9.6-fold (p\u2009\u2264\u20090.0001) and 25-fold (p\u2009\u2264\u20090.0001) increases in <jats:italic>CX3CL1<\/jats:italic> gene expression, and 1.9-fold (p\u2009=\u20090.0005) and 196-fold (p\u2009\u2264\u20090.0001) increases in CX3CL1 protein expression, respectively. Moreover, exposure of HCE-T cells to recombinant human CTSS at activity equivalent to that in SS patient tears increased cellular CX3CL1 gene and protein expression by 2.8-fold (p\u2009=\u20090.0021) and 5.1-fold (p\u2009\u2264\u20090.0001), while increasing CX3CL1 in culture medium by 5.8-fold (p\u2009\u2264\u20090.0001). Flow cytometry demonstrated a 4.5-fold increase in CX3CR1-expressing immune cells (p\u2009\u2264\u20090.0001), including increased T-cells and macrophages, in LG from NOD mice relative to BALB\/c. CTSS-mediated induction\/cleavage of CX3CL1 may contribute to ocular surface and LG inflammation in SS.<\/jats:p>","DOI":"10.1038\/s41598-020-58337-4","type":"journal-article","created":{"date-parts":[[2020,1,29]],"date-time":"2020-01-29T11:08:02Z","timestamp":1580296082000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Cathepsin S activation contributes to elevated CX3CL1 (fractalkine) levels in tears of a Sj\u00f6gren\u2019s syndrome murine model"],"prefix":"10.1038","volume":"10","author":[{"given":"Runzhong","family":"Fu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srikanth","family":"Janga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minchang","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wannita","family":"Klinngam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria C.","family":"Edman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah F.","family":"Hamm-Alvarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,29]]},"reference":[{"key":"58337_CR1","doi-asserted-by":"publisher","first-page":"16047","DOI":"10.1038\/nrdp.2016.47","volume":"2","author":"P Brito-Zer\u00f3n","year":"2016","unstructured":"Brito-Zer\u00f3n, P. et al. 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