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A Small Peptide Antagonist of the Fas Receptor Inhibits Neuroinflammation

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A Small Peptide Antagonist of the Fas Receptor Inhibits Neuroinflammation University of Massachusetts Medical School eScholarship@UMMS Open Access Articles Open Access Publications by UMMS Authors 2019-09-30 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 Anitha Krishnan Harvard Medical School Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/oapubs Part of the Amino Acids, Peptides, and Proteins Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Cell Biology Commons, Eye Diseases Commons, Nervous System Commons, Neuroscience and Neurobiology Commons, and the Ophthalmology Commons Repository Citation Krishnan A, Kocab AJ, Zacks DN, Marshak-Rothstein A, Gregory-Ksander M. (2019). 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. Open Access Articles. https://doi.org/ 10.1186/s12974-019-1576-3. Retrieved from https://escholarship.umassmed.edu/oapubs/3987 Creative Commons License This work is licensed under a Creative Commons Attribution 4.0 License. This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Open Access Articles by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. Krishnan et al. Journal of Neuroinflammation (2019) 16:184 https://doi.org/10.1186/s12974-019-1576-3 RESEARCH Open Access 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 Anitha Krishnan1, Andrew J. Kocab2, David N. Zacks3, Ann Marshak-Rothstein4 and Meredith Gregory-Ksander1* Abstract Background: Glaucoma is a complex, multifactorial disease where apoptosis, microglia activation, and inflammation have been linked to the death of retinal ganglion cells (RGCs) and axon degeneration. 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. Methods: Intracameral injection of microbeads was used to elevate intraocular pressure (IOP) in Fas-deficient (Faslpr) mice and WT C57BL/6J mice that received an intravitreal injection of the Fas inhibitor, ONL1204 (2 μg/1 μl) (or vehicle only), on day 0 or day 7 after microbead injection. The IOP was monitored by rebound tonometry, and at 28 days 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). Results: Rebound tonometry showed equivalent elevation of IOP in all groups of microbead-injected mice. At 28 days post-microbead injection, the RGC and axon counts from microbead-injected Faslpr 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, TNFα, IL-1β, IL-6, IL-18, MIP-1α, MIP-1β, MIP-2, MCPI, and IP10), components of the complement cascade (C3, C1Q), Toll-like receptor pathway (TLR4), and inflammasome pathway (NLRP3). (Continued on next page) * Correspondence: [email protected] 1Department of Ophthalmology, The Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA, USA Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Krishnan et al. Journal of Neuroinflammation (2019) 16:184 Page 2 of 15 (Continued from previous page) Conclusions: 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. Keywords: Glaucoma, Neuroprotection, Retinal ganglion cell, Fas ligand, Fas receptor, Apoptosis, Neuroinflammation, Neurodegeneration, Microglia, Immune privilege, Background (ONH) and retina [14–19] and the extent of microglia Glaucoma is the leading cause of irreversible blindness activation correlates with the extent of neurodegenera- worldwide, characterized by the progressive loss of ret- tion [20, 21]. Moreover, blocking microglia activation inal ganglion cells (RGCs). A recent study estimates that with minocycline [14, 20]oranti-TNFα [22, 23]pre- approximately 60 million people worldwide currently vents the infiltration of immune cells and significantly suffer from glaucoma, and with the rapidly growing reduces axon degeneration and death of RGCs in ex- aging population, this number is predicted to exceed 100 perimental models of glaucoma. Together, these data million by 2040 [1]. Elevated intraocular pressure (IOP) suggest that activated microglia are the driving force is a major risk factor for the development of glaucoma, behind glaucomatous neurodegeneration. However, and lowering IOP remains the only treatment for this the molecular mechanism(s) that mediate microglia disease [2]. However, the continued progression of the reactivity in glaucoma are not well understood. disease in some patients despite successful reduction of Fas ligand (FasL) is a type II transmembrane protein of IOP [3], combined with the increasing incidence of the TNF family, which is best known for its ability to in- normal-tension glaucoma [4, 5] and the absence of neu- duce apoptosis upon binding to the Fas receptor [24–27]. rodegeneration in some patients with elevated IOP [6], However, we demonstrated that within the eye, FasL can be indicates that IOP-independent mechanisms contribute expressed as a membrane-bound protein (mFasL), which is to the initiation and progression of glaucoma. Therefore, pro-apoptotic and pro-inflammatory, or it can be cleaved a current priority in the glaucoma field is to further de- and released as a soluble isoform (sFasL), which is non- fine the molecular mechanisms of RGC death and axon apoptotic and non-inflammatory [28–30]. In the normal degeneration in order to develop IOP-independent immune-privileged eye, where inflammation is tightly regu- therapeutic treatment strategies to halt disease progres- lated, FasL is primarily expressed as the non-apoptotic, sion and preserve vision. non-inflammatory sFasL [31]. However, in the DBA/2J There is substantial evidence that apoptosis of RGCs is mouse model of glaucoma, a shift in the expression of FasL the final common pathway in both human and experimen- from the soluble form to the proapoptotic and proinflam- tal models of glaucoma [7–10]. However, using the DBA/2J matory membrane form coincides with the loss of immune mouse model of spontaneous glaucoma, Libby et al. dem- privilege and the development of glaucoma [31, 32]. These onstrated that genetic ablation of the proapoptotic mol- data suggest mFasL activation of the Fas receptor plays a ecule BCL2-associated X protein (BAX) prevents apoptosis central role in the pathogenesis of glaucoma. Moreover, of RGCs, but does not prevent axon degeneration [11]. treating mice with sFasL, via intravitreal adeno-associated Similarly, McKinnon et al. demonstrated that gene therapy virus-mediated gene delivery, provided significant neuro- with a potent caspase inhibitor, baculoviral IAP repeat- protection of RGCs and axons, and this protection corre- containing protein-4 (BIRC4), only protects about 50% of lated with inhibition of retinal glial activation and the the RGCs and optic nerve axons in a rodent model of ele- induction of the proinflammatory mediators [31]. These vated IOP [12]. Therefore, while RGC apoptosis is the com- data demonstrate that blocking mFasL activation of the Fas mon endpoint in glaucoma, therapeutic approaches that receptor inhibits three hallmarks of glaucomatous degener- only target the apoptotic pathway in RGCs do not com- ation: microglia activation, inflammation, and apoptosis. pletely prevent glaucomatous neurodegeneration. Therefore, we hypothesized that
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