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Jiangang Wang, Ratanmani Joshi, John D. Ash; Stressed-Induced Neuroprotection through the LIF/GP130/STAT3 Pathway is Mediated by TLR2 Signaling. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1662.
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We have previously shown that the GP130 receptor and STAT3 are part of an inducible protective pathway that is essential for delaying inherited retinal degeneration. This pathway is activated by upregulation of leukemia inhibitory factor (LIF) in Muller cells in response to cellular stress caused by a genetic mutation or oxidative injury in neurons. The purpose of this study is to investigate whether toll like receptor 2 (TLR2) is part of the signaling cascade by which stressed neurons signal Muller cells to induce LIF expression.
Adult albino mice were exposed to damaging light (4000 lux) for 5 hours following 2 days after TLR2 agonist Pam3CYS injection. GP130 was specifically deleted from retina by CHX10-cre driven recombination of a floxed gp130 allele. Electroretinography was measured to identify the retinal function and retinal histology was used to quantify the photoreceptor loss. For gene expression profile after injection, retinas were collected before and 2 days after injection. Total RNA was extracted using Trizol (Invitrogen) and Real-time PCR was used to confirm expression changes.
Activation of TLR2 by its agonist Pam3CYS strongly rescued photoreceptor function and cells from light induced cell death. Expression analyses show that a broad spectrum of cytokines including IL-6 family cytokines were remarkably upregulated by Pam3CYS. In the absence of TLR2, LIF expression was not induced by light stress, and retinas were more sensitive to light damage. The neuroprotective effects of Pam3CYS were dependent on gp130 activation.
The results suggest that activation of TLR2 on Muller glial cells is necessary for oxidative stress induced expression of LIF. The study suggests a model where stressed neurons release ligands of TLR2, which when activated in Muller cells leads to increased LIF expression. Increased LIF then activates gp130 on neurons to induce protection.
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