Abstract
Toll-like receptor 4 (Tlr4) plays an important role in ischemia–reperfusion (IR)-induced retinal inflammation and damage. However, the role of two Tlr4-dependent signaling cascades, myeloid differentiation primary response 88 (Myd88) and TIR-domain-containing adapter inducing interferon-β (Trif), in retinal IR injury is poorly understood. In this study, we investigated the contribution of the Myd88-dependent and Trif-dependent signaling cascades in retinal damage and inflammation triggered by IR, by using Myd88 knockout (Myd88KO) and Trif knockout (TrifKO) mice. Retinal IR injury was induced by unilateral elevation of intraocular pressure for 45 min by direct corneal cannulation. To study IR-induced retinal ganglion cell (RGC) death in vitro, we used an oxygen and glucose deprivation (OGD) model. Our data suggested that Myd88 was present in many retinal layers of sham-operated and ischemic mice, whereas Trif was mainly present in the ganglion cell layer (GCL). The level of Myd88 was increased in the retina after IR. We found that retinas of TrifKO mice had a significantly reduced neurotoxic pro-inflammatory response and significantly increased survival of the GCL neurons after IR. Although Myd88KO mice had relatively low levels of inflammation in ischemic retinas, their levels of IR-induced retinal damage were notably higher than those of TrifKO mice. We also found that Trif-deficient RGCs were more resistant to death induced by OGD than were RGCs isolated from Myd88KO mice. These data suggested that, as compared with the Myd88-dependent signaling cascade, Trif signaling contributes significantly to retinal damage after IR.
Highlights
Retinal ischemia–reperfusion (IR) injury is a clinical condition that frequently causes blindness, owing to ineffective treatment (Osborne et al, 2004)
We found that expression of myeloid differentiation primary response 88 (Myd88) was upregulated in ischemic retinas, whereas the expression of TIR-domain-containing adapter inducing interferon-b (Trif) was not altered (Fig. 1A)
Results are expressed as a percentage of the corresponding value for Tlr1 expression in the sham-operated retina Æ SE of the mean (**P < 0.01, *P < 0.05, n = 6). (C) Micrograph of the gel-separated PCR products from the Quantitative reverse transcription polymerase chain reaction (qRT-PCR) test showing specific bands corresponding to mRNA for Tlr3, Thy1 (RGC marker), Gfap and Cd11b detected in the total RNA samples isolated from 500 and 100 microglial cells, astrocytes, and retinal ganglion cell (RGC)
Summary
Retinal ischemia–reperfusion (IR) injury is a clinical condition that frequently causes blindness, owing to ineffective treatment (Osborne et al, 2004). Toll-like receptors are a family of pattern recognition receptors that initiate an innate immune response in the presence of exogenous (pathogens) and endogenous (damage-associated molecular patterns) ligands (Janeway & Medzhitov, 2002; Piccinini & Midwood, 2010). Among toll-like receptors, Tlr is the most studied, and its critical role in IR-triggered damage and sterile inflammation in the retina has been acknowledged (Dvoriantchikova et al, 2010b; Ishizuka et al, 2013). The role of Tlr4-dependent signaling cascades in IR-induced retinal injury, has not been identified. Understanding the contribution of Tlr4-dependent signaling cascades in retinal IR injury will provide substantial insights and novel therapeutic strategies for this serious and difficult-to-treat condition
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
