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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.
J Neuroinflammation. 2019 Sep 30; 16(1):184.JN

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).

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.

Authors+Show Affiliations

Department of Ophthalmology, The Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA, USA.ONL Therapeutics, Ann Arbor, MI, USA.Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA.Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.Department of Ophthalmology, The Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA, USA. meredith_gregory@meei.harvard.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31570110

Citation

Krishnan, Anitha, et al. "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." Journal of Neuroinflammation, vol. 16, no. 1, 2019, p. 184.
Krishnan A, Kocab AJ, Zacks DN, et al. 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. J Neuroinflammation. 2019;16(1):184.
Krishnan, A., Kocab, A. J., Zacks, D. N., 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. Journal of Neuroinflammation, 16(1), 184. https://doi.org/10.1186/s12974-019-1576-3
Krishnan A, et al. 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. J Neuroinflammation. 2019 Sep 30;16(1):184. PubMed PMID: 31570110.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Krishnan,Anitha, AU - Kocab,Andrew J, AU - Zacks,David N, AU - Marshak-Rothstein,Ann, AU - Gregory-Ksander,Meredith, Y1 - 2019/09/30/ PY - 2019/05/14/received PY - 2019/08/29/accepted PY - 2019/10/2/entrez PY - 2019/10/2/pubmed PY - 2020/3/24/medline KW - Apoptosis KW - Fas ligand KW - Fas receptor KW - Glaucoma KW - Immune privilege KW - Microglia KW - Neurodegeneration KW - Neuroinflammation KW - Neuroprotection KW - Retinal ganglion cell SP - 184 EP - 184 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 16 IS - 1 N2 - 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). 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. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/31570110/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_ L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-019-1576-3 DB - PRIME DP - Unbound Medicine ER -