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We demonstrated previously that FasL-Fas signaling was required for axon degeneration and death of RGCs in chronic and inducible mouse models of glaucoma and that Fas activation triggered RGC apoptosis, glial activation, and inflammation. Here, we investigated whether targeting the Fas receptor with a small peptide antagonist, ONL1204, has anti-inflammatory and neuroprotective effects in a microbead-induced mouse model of glaucoma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Intracameral injection of microbeads was used to elevate intraocular pressure (IOP) in Fas-deficient (Fas\n                      <jats:sup>lpr<\/jats:sup>\n                      ) mice and WT C57BL\/6J mice that received an intravitreal injection of the Fas inhibitor, ONL1204 (2\u2009\u03bcg\/1\u2009\u03bcl) (or vehicle only), on day 0 or day 7 after microbead injection. The IOP was monitored by rebound tonometry, and at 28\u2009days post-microbead injection, Brn3a-stained RGCs and paraphenylenediamine (PPD)-stained axons were analyzed. The effects of ONL1204 on retinal microglia activation and the expression of inflammatory genes were analyzed by immunostaining of retinal flatmounts and quantitative PCR (qPCR).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Rebound tonometry showed equivalent elevation of IOP in all groups of microbead-injected mice. At 28\u2009days post-microbead injection, the RGC and axon counts from microbead-injected Fas\n                      <jats:sup>lpr<\/jats:sup>\n                      mice were equivalent to saline-injected (no IOP elevation) controls. Treatment with ONL1204 also significantly reduced RGC death and loss of axons in microbead-injected WT mice when compared to vehicle-treated controls, even when administered after IOP elevation. Confocal analysis of Iba1-stained retinal flatmounts and qPCR demonstrated that ONL1204 also abrogated microglia activation and inhibited the induction of multiple genes implicated in glaucoma, including cytokines and chemokines (GFAP, Caspase-8, TNF\u03b1, IL-1\u03b2, IL-6, IL-18, MIP-1\u03b1, MIP-1\u03b2, MIP-2, MCPI, and IP10), components of the complement cascade (C3, C1Q), Toll-like receptor pathway (TLR4), and inflammasome pathway (NLRP3).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results serve as proof-of-principal that the small peptide inhibitor of the Fas receptor, ONL1204, can provide robust neuroprotection in an inducible mouse model of glaucoma, even when administered after IOP elevation. Moreover, Fas signaling contributes to the pathogenesis of glaucoma through activation of both apoptotic and inflammatory pathways.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-019-1576-3","type":"journal-article","created":{"date-parts":[[2019,9,30]],"date-time":"2019-09-30T22:54:46Z","timestamp":1569884086000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":134,"title":["A small peptide antagonist of the Fas receptor inhibits neuroinflammation and prevents axon degeneration and retinal ganglion cell death in an inducible mouse model of glaucoma"],"prefix":"10.1186","volume":"16","author":[{"given":"Anitha","family":"Krishnan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Kocab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David N.","family":"Zacks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Marshak-Rothstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7193-0032","authenticated-orcid":false,"given":"Meredith","family":"Gregory-Ksander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,9,30]]},"reference":[{"key":"1576_CR1","doi-asserted-by":"publisher","first-page":"2081","DOI":"10.1016\/j.ophtha.2014.05.013","volume":"121","author":"Y-C Tham","year":"2014","unstructured":"Tham Y-C, Li X, Wong TY, Quigley HA, Aung T, Cheng C-Y. 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DNZ is a co-founder, equity holder, and consultant to ONL Therapeutics. Dr. Zacks is also a co-inventor on ONL\u2019s patent applications, as well as on patents and applications licensed by ONL Therapeutics from the University of Michigan and Massachusetts Eye and Ear that are based on the development and use of novel Fas inhibitors. MGK received a sponsored research grant from ONL Therapeutics. AK, AJK, DNZ, MGK are co-inventors on two patent applications submitted by ONL Therapeutics based in part on the results reported herein. MGK and AMR are co-inventors on a patent application on soluble Fas ligand as a neuroprotective therapeutic that has been licensed by ONL Therapeutics from University of Medical School Worcester and Massachusetts Eye and Ear.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"184"}}