Etanercept, a Widely Used Inhibitor of Tumor Necrosis Factor-α (TNF- α), Prevents Retinal Ganglion Cell Loss in a Rat Model of Glaucoma

Roh, Miin; Zhang, Yan; Murakami, Yusuke; Thanos, Aristomenis; Lee, Sung Chul; Vavvas, Demetrios G.; Benowitz, Larry I.; Miller, Joan W.

doi:10.1371/journal.pone.0040065

Cited by 184 publications

(169 citation statements)

References 61 publications

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“…TNF-α and TGF-β are both highly abundant in the aqueous humor of patients with both acute and chronic forms of glaucoma (33)(34)(35). To determine whether the expression of TNF-α was up-regulated in response to pressure, its transcript levels were measured by quantitative RT-PCR (qRT-PCR) under different pressures.…”

Section: Resultsmentioning

confidence: 99%

Primary cilia signaling mediates intraocular pressure sensation

Luo

Conwell

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

102

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Lowe syndrome is a rare X-linked congenital disease that presents with congenital cataracts and glaucoma, as well as renal and cerebral dysfunction. OCRL, an inositol polyphosphate 5-phosphatase, is mutated in Lowe syndrome. We previously showed that OCRL is involved in vesicular trafficking to the primary cilium. Primary cilia are sensory organelles on the surface of eukaryotic cells that mediate mechanotransduction in the kidney, brain, and bone. However, their potential role in the trabecular meshwork (TM) in the eye, which regulates intraocular pressure, is unknown. Here, we show that TM cells, which are defective in glaucoma, have primary cilia that are critical for response to pressure changes. Primary cilia in TM cells shorten in response to fluid flow and elevated hydrostatic pressure, and promote increased transcription of TNF-α, TGF-β, and GLI1 genes. Furthermore, OCRL is found to be required for primary cilia to respond to pressure stimulation. The interaction of OCRL with transient receptor potential vanilloid 4 (TRPV4), a ciliary mechanosensory channel, suggests that OCRL may act through regulation of this channel. A novel disease-causing OCRL allele prevents TRPV4-mediated calcium signaling. In addition, TRPV4 agonist GSK 1016790A treatment reduced intraocular pressure in mice; TRPV4 knockout animals exhibited elevated intraocular pressure and shortened cilia. Thus, mechanotransduction by primary cilia in TM cells is implicated in how the eye senses pressure changes and highlights OCRL and TRPV4 as attractive therapeutic targets for the treatment of glaucoma. Implications of OCRL and TRPV4 in primary cilia function may also shed light on mechanosensation in other organ systems.

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Section: Resultsmentioning

confidence: 99%

Primary cilia signaling mediates intraocular pressure sensation

Luo

Conwell

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

102

View full text Add to dashboard Cite

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“…In a mouse model of glaucoma, TNFa was found to mediate the cytotoxic effects of elevated IOP on ganglion cells, and injection of TNFa led to ganglion cell death and optic neuropathy (Nakazawa et al 2006). The source of the TNFa in the retina seems to be a population of microglia that resides around the ONH and becomes activated in ocular hypertension (Roh et al 2012). Importantly, the TNFa-decoy receptor etanercept prevents ganglion cell loss and optic nerve pathology in this model (Roh et al 2012).…”

Section: Differential Gene Expression In Glaucomamentioning

confidence: 95%

Differential Gene Expression in Glaucoma

Jakobs

2014

Cold Spring Harbor Perspectives in Medicine

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In glaucoma, regardless of its etiology, retinal ganglion cells degenerate and eventually die. Although age and elevated intraocular pressure (IOP) are the main risk factors, there are still many mysteries in the pathogenesis of glaucoma. The advent of genome-wide microarray expression screening together with the availability of animal models of the disease has allowed analysis of differential gene expression in all parts of the eye in glaucoma. This review will outline the findings of recent genome-wide expression studies and discuss their commonalities and differences. A common finding was the differential regulation of genes involved in inflammation and immunity, including the complement system and the cytokines transforming growth factor b (TGFb) and tumor necrosis factor a (TNFa). Other genes of interest have roles in the extracellular matrix, cell -matrix interactions and adhesion, the cell cycle, and the endothelin system.

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“…Genetic and pharmaceutical inhibition of TNFa activity in experimental models of glaucoma can prevent microglia activation, axonal degeneration and RGC loss (Fig. 3) (Nakazawa et al 2006;Roh et al 2012). Another member of the TNF family implicated in glaucoma pathogenesis is the proapoptotic protein Fas ligand, which was found to be damaging to RGCs in DBA/2J glaucoma (Gregory et al 2011).…”

Section: Inflammatory Signaling Pathways In Glaucomamentioning

confidence: 99%

“…However, this study was not able to distinguish between resident microglia and infiltrating monocytes. The mechanism(s) by which monocytes affect RGCs in glaucoma has not been (Roh et al 2012). Mann-Whitney U test, ÃÃ P , 0.01 comparing control vs. Etanercept treated ocular hypertension; † † P , 0.01 comparing vehicle vs. Etanercept treated OHT.…”

Section: Transendothelial Migration Of Leukocytes In Glaucomamentioning

confidence: 99%