{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T06:46:19Z","timestamp":1747205179579,"version":"3.40.5"},"posted":{"date-parts":[[2024,6,18]]},"group-title":"In Review","reference-count":66,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T00:00:00Z","timestamp":1718668800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,5,12]]},"abstract":"<title>Abstract<\/title>\n        <p>Background\n - Glaucoma is a complex multifactorial disease where apoptosis and inflammation represent two key pathogenic mechanisms. However, the relative contribution of apoptosis versus inflammation in axon degeneration and death of retinal ganglion cells (RGCs) is not well understood. In glaucoma, caspase-8 is linked to RGC apoptosis, as well as glial activation and neuroinflammation. To uncouple these two pathways and determine the extent to which caspase-8-mediated inflammation and\/or apoptosis contributes to the death of RGCs, we used the caspase-8 D387A mutant mouse (<italic>Casp8<\/italic><sup><italic>DA\/DA<\/italic><\/sup>) in which a point mutation in the auto-cleavage site blocks caspase-8-mediated apoptosis but does not block caspase-8-mediated inflammation.\nMethods-\n Intracameral injection of magnetic microbeads was used to elevate the intraocular pressure (IOP) in wild-type, Fas deficient Fas<sup>lpr<\/sup>, and <italic>Casp8<\/italic><sup><italic>DA\/DA<\/italic><\/sup> mice. IOP was monitored by rebound tonometry. Two weeks post microbead injection, retinas were collected for microglia activation analysis. Five weeks post microbead injection, visual acuity and RGC function were assessed by optometer reflex (OMR) and pattern electroretinogram (pERG), respectively. Retina and optic nerves were processed for RGC and axon quantification. Two- and five-weeks post microbead injection, expression of the necrosis marker, RIPK3, was assessed by qPCR.\nResults-\n Wild-type, Fas<sup>lpr<\/sup>, and <italic>Casp8<\/italic><sup><italic>DA\/DA<\/italic><\/sup> mice showed similar IOP elevation as compared to saline controls. A significant reduction in both visual acuity and pERG that correlated with a significant loss of RGCs and axons was observed in wild-type but not in Fas<sup>lpr<\/sup> mice. The <italic>Casp8<\/italic><sup><italic>DA\/DA<\/italic><\/sup> mice displayed a significant reduction in visual acuity and pERG amplitude and loss of RGCs and axons similar to that in wild-type mice. Immunostaining revealed equal numbers of activated microglia, double positive for P2ry12 and IB4, in the retinas from microbead-injected wild-type and <italic>Casp8<\/italic><sup><italic>DA\/DA<\/italic><\/sup> mutant mice. qPCR analysis revealed no induction of RIPK3 in wild-type or <italic>Casp8<\/italic><sup><italic>DA\/DA<\/italic><\/sup> mice at two- or five-weeks post microbead injection.\nConclusions-\n Our results demonstrate that caspase-8-mediated extrinsic apoptosis is not involved in the death of RGCs in the microbead-induced mouse model of glaucoma implicating caspase-8-mediated inflammation, but not apoptosis, as the driving force in glaucoma progression. Taken together, these results identify the caspase-8-mediated inflammatory pathway as a potential target for neuroprotection in glaucoma.<\/p>","DOI":"10.21203\/rs.3.rs-4409426\/v1","type":"posted-content","created":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T15:44:30Z","timestamp":1718984670000},"source":"Crossref","is-referenced-by-count":0,"title":["Caspase-8-mediated inflammation but not apoptosis drives death of retinal ganglion cells and loss of visual function in glaucomaa"],"prefix":"10.21203","author":[{"given":"Yinjie","family":"Guo","sequence":"first","affiliation":[{"name":"Xiangya Hospital Central South University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5280-2836","authenticated-orcid":false,"given":"Bhupender","family":"Verma","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute of Massachusetts Eye and Ear"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maleeka","family":"Shrestha","sequence":"additional","affiliation":[{"name":"Harvard University HSPH: Harvard University T H Chan School of Public Health"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ann","family":"Marshak-Rothstein","sequence":"additional","affiliation":[{"name":"University of Massachusetts Chan Medical School Department of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7193-0032","authenticated-orcid":false,"given":"Meredith","family":"Gregory-Ksander","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute of Massachusetts Eye and Ear"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","reference":[{"issue":"1","key":"ref1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1371\/journal.pgen.0010004","article-title":"Susceptibility to neurodegeneration in a glaucoma is modified by Bax gene dosage","volume":"1","author":"Libby RT","year":"2005","unstructured":"Libby RT, Li Y, Savinova OV, Barter J, Smith RS, Nickells RW, John SW. Susceptibility to neurodegeneration in a glaucoma is modified by Bax gene dosage. PLoS Genet. 2005;1(1):17\u201326.","journal-title":"PLoS Genet"},{"issue":"5","key":"ref2","first-page":"774","article-title":"Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis","volume":"36","author":"Quigley HA","year":"1995","unstructured":"Quigley HA, Nickells RW, Kerrigan LA, Pease ME, Thibault DJ, Zack DJ. Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci. 1995;36(5):774\u201386.","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"8","key":"ref3","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1001\/archopht.1997.01100160201010","article-title":"TUNEL-positive ganglion cells in human primary open-angle glaucoma","volume":"115","author":"Kerrigan LA","year":"1997","unstructured":"Kerrigan LA, Zack DJ, Quigley HA, Smith SD, Pease ME. TUNEL-positive ganglion cells in human primary open-angle glaucoma. Arch Ophthalmol. 1997;115(8):1031\u20135.","journal-title":"Arch Ophthalmol"},{"issue":"Suppl 3","key":"ref4","doi-asserted-by":"crossref","first-page":"S268","DOI":"10.1016\/S0039-6257(01)00204-1","article-title":"In situ detection of apoptosis in normal pressure glaucoma. a preliminary examination","volume":"45","author":"Tatton NA","year":"2001","unstructured":"Tatton NA, Tezel G, Insolia SA, Nandor SA, Edward PD, Wax MB. In situ detection of apoptosis in normal pressure glaucoma. a preliminary examination. Surv Ophthalmol. 2001;45(Suppl 3):S268\u201372. discussion S73-6.","journal-title":"Surv Ophthalmol"},{"issue":"7","key":"ref5","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1083\/jcb.200706181","article-title":"Axons of retinal ganglion cells are insulted in the optic nerve early in DBA\/2J glaucoma","volume":"179","author":"Howell GR","year":"2007","unstructured":"Howell GR, Libby RT, Jakobs TC, Smith RS, Phalan FC, Barter JW, et al. Axons of retinal ganglion cells are insulted in the optic nerve early in DBA\/2J glaucoma. J Cell Biol. 2007;179(7):1523\u201337.","journal-title":"J Cell Biol"},{"issue":"11","key":"ref6","doi-asserted-by":"crossref","first-page":"2735","DOI":"10.1523\/JNEUROSCI.4443-07.2008","article-title":"Progressive ganglion cell degeneration precedes neuronal loss in a mouse model of glaucoma","volume":"28","author":"Buckingham BP","year":"2008","unstructured":"Buckingham BP, Inman DM, Lambert W, Oglesby E, Calkins DJ, Steele MR, et al. Progressive ganglion cell degeneration precedes neuronal loss in a mouse model of glaucoma. J Neurosci. 2008;28(11):2735\u201344.","journal-title":"J Neurosci"},{"issue":"2","key":"ref7","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1523\/JNEUROSCI.3714-07.2008","article-title":"Retinal ganglion cells downregulate gene expression and lose their axons within the optic nerve head in a mouse glaucoma model","volume":"28","author":"Soto I","year":"2008","unstructured":"Soto I, Oglesby E, Buckingham BP, Son JL, Roberson ED, Steele MR, et al. Retinal ganglion cells downregulate gene expression and lose their axons within the optic nerve head in a mouse glaucoma model. J Neurosci. 2008;28(2):548\u201361.","journal-title":"J Neurosci"},{"issue":"2","key":"ref8","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1083\/jcb.200506099","article-title":"Retinal ganglion cell degeneration is topological but not cell type specific in DBA\/2J mice","volume":"171","author":"Jakobs TC","year":"2005","unstructured":"Jakobs TC, Libby RT, Ben Y, John SW, Masland RH. Retinal ganglion cell degeneration is topological but not cell type specific in DBA\/2J mice. J Cell Biol. 2005;171(2):313\u201325.","journal-title":"J Cell Biol"},{"issue":"11","key":"ref9","doi-asserted-by":"crossref","first-page":"5196","DOI":"10.1073\/pnas.0913141107","article-title":"Distal axonopathy with structural persistence in glaucomatous neurodegeneration","volume":"107","author":"Crish SD","year":"2010","unstructured":"Crish SD, Sappington RM, Inman DM, Horner PJ, Calkins DJ. Distal axonopathy with structural persistence in glaucomatous neurodegeneration. Proc Natl Acad Sci U S A. 2010;107(11):5196\u2013201.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"9774","key":"ref10","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1016\/S0140-6736(10)61423-7","volume":"377","author":"Quigley HA","year":"2011","unstructured":"Quigley HA. Glaucoma Lancet. 2011;377(9774):1367\u201377.","journal-title":"Glaucoma Lancet"},{"issue":"5","key":"ref11","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1002\/jnr.1104","article-title":"Activated microglia in the human glaucomatous optic nerve head","volume":"64","author":"Yuan L","year":"2001","unstructured":"Yuan L, Neufeld AH. Activated microglia in the human glaucomatous optic nerve head. J Neurosci Res. 2001;64(5):523\u201332.","journal-title":"J Neurosci Res"},{"issue":"9","key":"ref12","first-page":"2962","article-title":"Detection of early neuron degeneration and accompanying microglial responses in the retina of a rat model of glaucoma","volume":"43","author":"Naskar R","year":"2002","unstructured":"Naskar R, Wissing M, Thanos S. Detection of early neuron degeneration and accompanying microglial responses in the retina of a rat model of glaucoma. Invest Ophthalmol Vis Sci. 2002;43(9):2962\u20138.","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"4","key":"ref13","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1172\/JCI61135","article-title":"Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma","volume":"122","author":"Howell GR","year":"2012","unstructured":"Howell GR, Soto I, Zhu X, Ryan M, Macalinao DG, Sousa GL, et al. Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma. J Clin Invest. 2012;122(4):1246\u201361.","journal-title":"J Clin Invest"},{"issue":"1","key":"ref14","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.coph.2012.09.013","article-title":"Immune regulation toward immunomodulation for neuroprotection in glaucoma","volume":"13","author":"Tezel G","year":"2013","unstructured":"Tezel G. Immune regulation toward immunomodulation for neuroprotection in glaucoma. Curr Opin Pharmacol. 2013;13(1):23\u201331.","journal-title":"Curr Opin Pharmacol"},{"issue":"5","key":"ref15","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1242\/dmm.018788","article-title":"Neurodegeneration severity can be predicted from early microglia alterations monitored in vivo in a mouse model of chronic glaucoma","volume":"8","author":"Bosco A","year":"2015","unstructured":"Bosco A, Romero CO, Breen KT, Chagovetz AA, Steele MR, Ambati BK, Vetter ML. Neurodegeneration severity can be predicted from early microglia alterations monitored in vivo in a mouse model of chronic glaucoma. Dis Model Mech. 2015;8(5):443\u201355.","journal-title":"Dis Model Mech"},{"issue":"2","key":"ref16","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/jnc.14070","article-title":"Involvement of microglia in early axoglial alterations of the optic nerve induced by experimental glaucoma","volume":"142","author":"Bordone MP","year":"2017","unstructured":"Bordone MP, Gonz\u00e1lez Fleitas MF, Pasquini LA, Bosco A, Sande PH, Rosenstein RE, Dorfman D. Involvement of microglia in early axoglial alterations of the optic nerve induced by experimental glaucoma. J Neurochem. 2017;142(2):323\u201337.","journal-title":"J Neurochem"},{"issue":"7","key":"ref17","doi-asserted-by":"crossref","first-page":"e40065","DOI":"10.1371\/journal.pone.0040065","article-title":"Etanercept, a widely used inhibitor of tumor necrosis factor-\u03b1 (TNF-\u03b1), prevents retinal ganglion cell loss in a rat model of glaucoma","volume":"7","author":"Roh M","year":"2012","unstructured":"Roh M, Zhang Y, Murakami Y, Thanos A, Lee SC, Vavvas DG, et al. Etanercept, a widely used inhibitor of tumor necrosis factor-\u03b1 (TNF-\u03b1), prevents retinal ganglion cell loss in a rat model of glaucoma. PLoS ONE. 2012;7(7):e40065.","journal-title":"PLoS ONE"},{"issue":"49","key":"ref18","doi-asserted-by":"crossref","first-page":"12633","DOI":"10.1523\/JNEUROSCI.2801-06.2006","article-title":"Tumor necrosis factor-alpha mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma","volume":"26","author":"Nakazawa T","year":"2006","unstructured":"Nakazawa T, Nakazawa C, Matsubara A, Noda K, Hisatomi T, She H, et al. Tumor necrosis factor-alpha mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma. J Neurosci. 2006;26(49):12633\u201341.","journal-title":"J Neurosci"},{"issue":"3","key":"ref19","doi-asserted-by":"crossref","first-page":"e17659","DOI":"10.1371\/journal.pone.0017659","article-title":"Opposing roles for membrane bound and soluble Fas ligand in glaucoma-associated retinal ganglion cell death","volume":"6","author":"Gregory MS","year":"2011","unstructured":"Gregory MS, Hackett CG, Abernathy EF, Lee KS, Saff RR, Hohlbaum AM, et al. Opposing roles for membrane bound and soluble Fas ligand in glaucoma-associated retinal ganglion cell death. PLoS ONE. 2011;6(3):e17659.","journal-title":"PLoS ONE"},{"issue":"12","key":"ref20","doi-asserted-by":"crossref","first-page":"4626","DOI":"10.4049\/jimmunol.1601488","article-title":"Overexpression of Soluble Fas Ligand following Adeno-Associated Virus Gene Therapy Prevents Retinal Ganglion Cell Death in Chronic and Acute Murine Models of Glaucoma","volume":"197","author":"Krishnan A","year":"2016","unstructured":"Krishnan A, Fei F, Jones A, Busto P, Marshak-Rothstein A, Ksander BR, Gregory-Ksander M. Overexpression of Soluble Fas Ligand following Adeno-Associated Virus Gene Therapy Prevents Retinal Ganglion Cell Death in Chronic and Acute Murine Models of Glaucoma. J Immunol. 2016;197(12):4626\u201338.","journal-title":"J Immunol"},{"issue":"1","key":"ref21","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1186\/s12974-019-1576-3","article-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","volume":"16","author":"Krishnan A","year":"2019","unstructured":"Krishnan A, Kocab AJ, Zacks DN, Marshak-Rothstein A, Gregory-Ksander M. 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.","journal-title":"J Neuroinflammation"},{"issue":"7","key":"ref22","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1084\/jem.191.7.1209","article-title":"Opposing effects of transmembrane and soluble Fas ligand expression on inflammation and tumor cell survival","volume":"191","author":"Hohlbaum AM","year":"2000","unstructured":"Hohlbaum AM, Moe S, Marshak-Rothstein A. Opposing effects of transmembrane and soluble Fas ligand expression on inflammation and tumor cell survival. J Exp Med. 2000;191(7):1209\u201320.","journal-title":"J Exp Med"},{"issue":"4","key":"ref23","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/ni1054","article-title":"Fas ligation on macrophages enhances IL-1R1-Toll-like receptor 4 signaling and promotes chronic inflammation","volume":"5","author":"Ma Y","year":"2004","unstructured":"Ma Y, Liu H, Tu-Rapp H, Thiesen HJ, Ibrahim SM, Cole SM, Pope RM. Fas ligation on macrophages enhances IL-1R1-Toll-like receptor 4 signaling and promotes chronic inflammation. Nat Immunol. 2004;5(4):380\u20137.","journal-title":"Nat Immunol"},{"issue":"1","key":"ref24","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1084\/jem.186.1.147","article-title":"Development of inflammatory angiogenesis by local stimulation of Fas in vivo","volume":"186","author":"Biancone L","year":"1997","unstructured":"Biancone L, Martino AD, Orlandi V, Conaldi PG, Toniolo A, Camussi G. Development of inflammatory angiogenesis by local stimulation of Fas in vivo. J Exp Med. 1997;186(1):147\u201352.","journal-title":"J Exp Med"},{"issue":"4","key":"ref25","doi-asserted-by":"crossref","first-page":"2326","DOI":"10.4049\/jimmunol.162.4.2326","article-title":"CD95 (Fas\/Apo-1) as a receptor governing astrocyte apoptotic or inflammatory responses: a key role in brain inflammation?","volume":"162","author":"Saas P","year":"1999","unstructured":"Saas P, Boucraut J, Quiquerez AL, Schnuriger V, Perrin G, Desplat-Jego S, et al. CD95 (Fas\/Apo-1) as a receptor governing astrocyte apoptotic or inflammatory responses: a key role in brain inflammation? J Immunol. 1999;162(4):2326\u201333.","journal-title":"J Immunol"},{"issue":"7343","key":"ref26","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/nature09788","article-title":"Caspase signalling controls microglia activation and neurotoxicity","volume":"472","author":"Burguillos MA","year":"2011","unstructured":"Burguillos MA, Deierborg T, Kavanagh E, Persson A, Hajji N, Garcia-Quintanilla A, et al. Caspase signalling controls microglia activation and neurotoxicity. Nature. 2011;472(7343):319\u201324.","journal-title":"Nature"},{"issue":"11","key":"ref27","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1016\/j.bcp.2008.07.034","article-title":"Non-apoptotic functions of caspase-8","volume":"76","author":"Maelfait J","year":"2008","unstructured":"Maelfait J, Beyaert R. Non-apoptotic functions of caspase-8. Biochem Pharmacol. 2008;76(11):1365\u201373.","journal-title":"Biochem Pharmacol"},{"issue":"1","key":"ref28","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/sj.cdd.4402047","article-title":"Caspases in cell survival, proliferation and differentiation","volume":"14","author":"Lamkanfi M","year":"2007","unstructured":"Lamkanfi M, Festjens N, Declercq W, Vanden Berghe T, Vandenabeele P. Caspases in cell survival, proliferation and differentiation. Cell Death Differ. 2007;14(1):44\u201355.","journal-title":"Cell Death Differ"},{"issue":"30","key":"ref29","doi-asserted-by":"crossref","first-page":"11181","DOI":"10.1073\/pnas.1402819111","article-title":"Caspase-8 promotes NLRP1\/NLRP3 inflammasome activation and IL-1beta production in acute glaucoma","volume":"111","author":"Chi W","year":"2014","unstructured":"Chi W, Li F, Chen H, Wang Y, Zhu Y, Yang X, et al. Caspase-8 promotes NLRP1\/NLRP3 inflammasome activation and IL-1beta production in acute glaucoma. Proc Natl Acad Sci U S A. 2014;111(30):11181\u20136.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1186\/s12974-015-0360-2","article-title":"HMGB1 promotes the activation of NLRP3 and caspase-8 inflammasomes via NF-kappaB pathway in acute glaucoma","volume":"12","author":"Chi W","year":"2015","unstructured":"Chi W, Chen H, Li F, Zhu Y, Yin W, Zhuo Y. HMGB1 promotes the activation of NLRP3 and caspase-8 inflammasomes via NF-kappaB pathway in acute glaucoma. J Neuroinflammation. 2015;12:137.","journal-title":"J Neuroinflammation"},{"issue":"4","key":"ref31","doi-asserted-by":"crossref","first-page":"2522","DOI":"10.4049\/jimmunol.181.4.2522","article-title":"Mutation of a self-processing site in caspase-8 compromises its apoptotic but not its nonapoptotic functions in bacterial artificial chromosome-transgenic mice","volume":"181","author":"Kang TB","year":"2008","unstructured":"Kang TB, Oh GS, Scandella E, Bolinger B, Ludewig B, Kovalenko A, Wallach D. Mutation of a self-processing site in caspase-8 compromises its apoptotic but not its nonapoptotic functions in bacterial artificial chromosome-transgenic mice. J Immunol. 2008;181(4):2522\u201332.","journal-title":"J Immunol"},{"issue":"10","key":"ref32","doi-asserted-by":"crossref","first-page":"e1005910","DOI":"10.1371\/journal.ppat.1005910","article-title":"Activity of Uncleaved Caspase-8 Controls Anti-bacterial Immune Defense and TLR-Induced Cytokine Production Independent of Cell Death","volume":"12","author":"Philip NH","year":"2016","unstructured":"Philip NH, DeLaney A, Peterson LW, Santos-Marrero M, Grier JT, Sun Y, et al. Activity of Uncleaved Caspase-8 Controls Anti-bacterial Immune Defense and TLR-Induced Cytokine Production Independent of Cell Death. PLoS Pathog. 2016;12(10):e1005910.","journal-title":"PLoS Pathog"},{"issue":"109","key":"ref33","first-page":"e53731","article-title":"A Magnetic Microbead Occlusion Model to Induce Ocular Hypertension-Dependent Glaucoma in Mice","author":"Ito YA","year":"2016","unstructured":"Ito YA, Belforte N, Cueva Vargas JL, Di Polo A. A Magnetic Microbead Occlusion Model to Induce Ocular Hypertension-Dependent Glaucoma in Mice. J Vis Exp. 2016(109):e53731.","journal-title":"J Vis Exp"},{"issue":"7","key":"ref34","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider CA","year":"2012","unstructured":"Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9(7):671\u20135.","journal-title":"Nat Methods"},{"issue":"6","key":"ref35","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C(T) method","volume":"3","author":"Schmittgen TD","year":"2008","unstructured":"Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101\u20138.","journal-title":"Nat Protoc"},{"issue":"22","key":"ref36","doi-asserted-by":"crossref","first-page":"5579","DOI":"10.1002\/j.1460-2075.1995.tb00245.x","article-title":"Cytotoxicity-dependent APO-1 (Fas\/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor","volume":"14","author":"Kischkel FC","year":"1995","unstructured":"Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME. Cytotoxicity-dependent APO-1 (Fas\/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. Embo j. 1995;14(22):5579\u201388.","journal-title":"Embo j"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"109273","DOI":"10.1016\/j.exer.2022.109273","article-title":"Microglia depletion exacerbates retinal ganglion cell loss in a mouse model of glaucoma","volume":"225","author":"Tan Z","year":"2022","unstructured":"Tan Z, Guo Y, Shrestha M, Sun D, Gregory-Ksander M, Jakobs TC. Microglia depletion exacerbates retinal ganglion cell loss in a mouse model of glaucoma. Exp Eye Res. 2022;225:109273.","journal-title":"Exp Eye Res"},{"issue":"4","key":"ref38","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1002\/cne.22516","article-title":"Early microglia activation in a mouse model of chronic glaucoma","volume":"519","author":"Bosco A","year":"2011","unstructured":"Bosco A, Steele MR, Vetter ML. Early microglia activation in a mouse model of chronic glaucoma. J Comp Neurol. 2011;519(4):599\u2013620.","journal-title":"J Comp Neurol"},{"issue":"43","key":"ref39","doi-asserted-by":"crossref","first-page":"E4098","DOI":"10.1073\/pnas.1308679110","article-title":"Phagocytosis executes delayed neuronal death after focal brain ischemia","volume":"110","author":"Neher JJ","year":"2013","unstructured":"Neher JJ, Emmrich JV, Fricker M, Mander PK, Th\u00e9ry C, Brown GC. Phagocytosis executes delayed neuronal death after focal brain ischemia. Proc Natl Acad Sci U S A. 2013;110(43):E4098\u2013107.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"ref40","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1073\/pnas.79.1.166","article-title":"Stimulated macrophages express a new glycoprotein receptor reactive with Griffonia simplicifolia I-B4 isolectin","volume":"79","author":"Maddox DE","year":"1982","unstructured":"Maddox DE, Shibata S, Goldstein IJ. Stimulated macrophages express a new glycoprotein receptor reactive with Griffonia simplicifolia I-B4 isolectin. Proc Natl Acad Sci U S A. 1982;79(1):166\u201370.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7338","key":"ref41","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/nature09852","article-title":"Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis","volume":"471","author":"Oberst A","year":"2011","unstructured":"Oberst A, Dillon CP, Weinlich R, McCormick LL, Fitzgerald P, Pop C, et al. Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis. Nature. 2011;471(7338):363\u20137.","journal-title":"Nature"},{"issue":"7784","key":"ref42","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/s41586-019-1770-6","article-title":"Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis","volume":"575","author":"Fritsch M","year":"2019","unstructured":"Fritsch M, G\u00fcnther SD, Schwarzer R, Albert MC, Schorn F, Werthenbach JP, et al. Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature. 2019;575(7784):683\u20137.","journal-title":"Nature"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"701564","DOI":"10.3389\/fphar.2021.701564","article-title":"Necroptosis: A Novel Pathway in Neuroinflammation","volume":"12","author":"Yu Z","year":"2021","unstructured":"Yu Z, Jiang N, Su W, Zhuo Y. Necroptosis: A Novel Pathway in Neuroinflammation. 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Immunity. 1998;9(2):267\u201376.","journal-title":"Immunity"},{"issue":"3","key":"ref45","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1042\/BJ20101738","article-title":"FLIP(L) induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity","volume":"433","author":"Pop C","year":"2011","unstructured":"Pop C, Oberst A, Drag M, Van Raam BJ, Riedl SJ, Green DR, Salvesen GS. FLIP(L) induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity. Biochem J. 2011;433(3):447\u201357.","journal-title":"Biochem J"},{"issue":"6","key":"ref46","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1006\/mthe.2002.0608","article-title":"Baculoviral IAP repeat-containing-4 protects optic nerve axons in a rat glaucoma model","volume":"5","author":"McKinnon SJ","year":"2002","unstructured":"McKinnon SJ, Lehman DM, Tahzib NG, Ransom NL, Reitsamer HA, Liston P, et al. Baculoviral IAP repeat-containing-4 protects optic nerve axons in a rat glaucoma model. Mol Ther. 2002;5(6):780\u20137.","journal-title":"Mol Ther"},{"issue":"12","key":"ref47","doi-asserted-by":"crossref","first-page":"5986","DOI":"10.1073\/pnas.94.12.5986","article-title":"Fas-ligand: privilege and peril","volume":"94","author":"Green DR","year":"1997","unstructured":"Green DR, Ware CF. Fas-ligand: privilege and peril. Proc Natl Acad Sci U S A. 1997;94(12):5986\u201390.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"105258","DOI":"10.1016\/j.nbd.2021.105258","article-title":"Regulation of distinct caspase-8 functions in retinal ganglion cells and astroglia in experimental glaucoma","volume":"150","author":"Yang X","year":"2021","unstructured":"Yang X, Zeng Q, Tezel G. Regulation of distinct caspase-8 functions in retinal ganglion cells and astroglia in experimental glaucoma. Neurobiol Dis. 2021;150:105258.","journal-title":"Neurobiol Dis"},{"issue":"1","key":"ref49","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.brainres.2006.02.051","article-title":"Calpeptin provides functional neuroprotection to rat retinal ganglion cells following Ca2\u2009+\u2009influx","volume":"1084","author":"Das A","year":"2006","unstructured":"Das A, Garner DP, Del Re AM, Woodward JJ, Kumar DM, Agarwal N, et al. Calpeptin provides functional neuroprotection to rat retinal ganglion cells following Ca2\u2009+\u2009influx. Brain Res. 2006;1084(1):146\u201357.","journal-title":"Brain Res"},{"issue":"6","key":"ref50","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1076\/ceyr.25.6.389.14233","article-title":"Activation of caspase 9 in a rat model of experimental glaucoma","volume":"25","author":"H\u00e4nninen VA","year":"2002","unstructured":"H\u00e4nninen VA, Pantcheva MB, Freeman EE, Poulin NR, Grosskreutz CL. Activation of caspase 9 in a rat model of experimental glaucoma. Curr Eye Res. 2002;25(6):389\u201395.","journal-title":"Curr Eye Res"},{"issue":"11","key":"ref51","doi-asserted-by":"crossref","first-page":"8442","DOI":"10.1167\/iovs.11-8152","article-title":"Neurodegenerative and inflammatory pathway components linked to TNF-\u03b1\/TNFR1 signaling in the glaucomatous human retina","volume":"52","author":"Yang X","year":"2011","unstructured":"Yang X, Luo C, Cai J, Powell DW, Yu D, Kuehn MH, Tezel G. Neurodegenerative and inflammatory pathway components linked to TNF-\u03b1\/TNFR1 signaling in the glaucomatous human retina. Invest Ophthalmol Vis Sci. 2011;52(11):8442\u201354.","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"3","key":"ref52","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/S0002-9440(10)62042-1","article-title":"Transcriptional up-regulation and activation of initiating caspases in experimental glaucoma","volume":"167","author":"Huang W","year":"2005","unstructured":"Huang W, Dobberfuhl A, Filippopoulos T, Ingelsson M, Fileta JB, Poulin NR, Grosskreutz CL. Transcriptional up-regulation and activation of initiating caspases in experimental glaucoma. Am J Pathol. 2005;167(3):673\u201381.","journal-title":"Am J Pathol"},{"issue":"4","key":"ref53","first-page":"1077","article-title":"Caspase activation and amyloid precursor protein cleavage in rat ocular hypertension","volume":"43","author":"McKinnon SJ","year":"2002","unstructured":"McKinnon SJ, Lehman DM, Kerrigan-Baumrind LA, Merges CA, Pease ME, Kerrigan DF, et al. 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BAX-Depleted Retinal Ganglion Cells Survive and Become Quiescent Following Optic Nerve Damage. Mol Neurobiol. 2020;57(2):1070\u201384.","journal-title":"Mol Neurobiol"},{"issue":"7","key":"ref56","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/sj.cdd.4400538","article-title":"Bax antisense oligonucleotides reduce axotomy-induced retinal ganglion cell death in vivo by reduction of Bax protein expression","volume":"6","author":"Isenmann S","year":"1999","unstructured":"Isenmann S, Engel S, Gillardon F, B\u00e4hr M. Bax antisense oligonucleotides reduce axotomy-induced retinal ganglion cell death in vivo by reduction of Bax protein expression. Cell Death Differ. 1999;6(7):673\u201382.","journal-title":"Cell Death Differ"},{"issue":"11","key":"ref57","first-page":"2660","article-title":"Inhibition of caspase activity in retinal cell apoptosis induced by various stimuli in vitro","volume":"40","author":"Tezel G","year":"1999","unstructured":"Tezel G, Wax MB. Inhibition of caspase activity in retinal cell apoptosis induced by various stimuli in vitro. Invest Ophthalmol Vis Sci. 1999;40(11):2660\u20137.","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"12","key":"ref58","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1038\/sj.cr.7310112","article-title":"Commonly used caspase inhibitors designed based on substrate specificity profiles lack selectivity","volume":"16","author":"Berger AB","year":"2006","unstructured":"Berger AB, Sexton KB, Bogyo M. Commonly used caspase inhibitors designed based on substrate specificity profiles lack selectivity. Cell Res. 2006;16(12):961\u20133.","journal-title":"Cell Res"},{"key":"ref59","doi-asserted-by":"crossref","first-page":"106989","DOI":"10.1016\/j.intimp.2020.106989","article-title":"Laquinimod exerts anti-inflammatory and antiapoptotic effects in retinal ischemia\/reperfusion injury","volume":"88","author":"Jiang N","year":"2020","unstructured":"Jiang N, Li Z, Li Z, Zhang Y, Yu Z, Wan P, et al. Laquinimod exerts anti-inflammatory and antiapoptotic effects in retinal ischemia\/reperfusion injury. Int Immunopharmacol. 2020;88:106989.","journal-title":"Int Immunopharmacol"},{"key":"ref60","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/1755-8794-2-24","article-title":"Network analysis of human glaucomatous optic nerve head astrocytes","volume":"2","author":"Nikolskaya T","year":"2009","unstructured":"Nikolskaya T, Nikolsky Y, Serebryiskaya T, Zvereva S, Sviridov E, Dezso Z, et al. Network analysis of human glaucomatous optic nerve head astrocytes. BMC Med Genomics. 2009;2:24.","journal-title":"BMC Med Genomics"},{"issue":"1","key":"ref61","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1002\/glia.10051","article-title":"Differential gene expression in astrocytes from human normal and glaucomatous optic nerve head analyzed by cDNA microarray","volume":"38","author":"Hernandez MR","year":"2002","unstructured":"Hernandez MR, Agapova OA, Yang P, Salvador-Silva M, Ricard CS, Aoi S. Differential gene expression in astrocytes from human normal and glaucomatous optic nerve head analyzed by cDNA microarray. Glia. 2002;38(1):45\u201364.","journal-title":"Glia"},{"issue":"8","key":"ref62","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1002\/glia.22507","article-title":"Reversible reactivity by optic nerve astrocytes","volume":"61","author":"Sun D","year":"2013","unstructured":"Sun D, Qu J, Jakobs TC. Reversible reactivity by optic nerve astrocytes. Glia. 2013;61(8):1218\u201335.","journal-title":"Glia"},{"issue":"6","key":"ref63","doi-asserted-by":"crossref","first-page":"e67094","DOI":"10.1371\/journal.pone.0067094","article-title":"The Time Course of Gene Expression during Reactive Gliosis in the Optic Nerve","volume":"8","author":"Qu J","year":"2013","unstructured":"Qu J, Jakobs TC. The Time Course of Gene Expression during Reactive Gliosis in the Optic Nerve. PLoS ONE. 2013;8(6):e67094.","journal-title":"PLoS ONE"},{"issue":"12","key":"ref64","doi-asserted-by":"crossref","first-page":"107776","DOI":"10.1016\/j.celrep.2020.107776","article-title":"Neurotoxic Reactive Astrocytes Drive Neuronal Death after Retinal Injury","volume":"31","author":"Guttenplan KA","year":"2020","unstructured":"Guttenplan KA, Stafford BK, El-Danaf RN, Adler DI, M\u00fcnch AE, Weigel MK, et al. Neurotoxic Reactive Astrocytes Drive Neuronal Death after Retinal Injury. Cell Rep. 2020;31(12):107776.","journal-title":"Cell Rep"},{"issue":"7999","key":"ref65","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1038\/s41586-023-06935-3","article-title":"A molecular switch for neuroprotective astrocyte reactivity","volume":"626","author":"Cameron EG","year":"2024","unstructured":"Cameron EG, Nahmou M, Toth AB, Heo L, Tanasa B, Dalal R, et al. A molecular switch for neuroprotective astrocyte reactivity. Nature. 2024;626(7999):574\u201382.","journal-title":"Nature"},{"issue":"12","key":"ref66","doi-asserted-by":"crossref","first-page":"3299","DOI":"10.1523\/JNEUROSCI.5572-05.2006","article-title":"Human astrocytes are resistant to Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis","volume":"26","author":"Song JH","year":"2006","unstructured":"Song JH, Bellail A, Tse MC, Yong VW, Hao C. Human astrocytes are resistant to Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. 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