Abstract
PurposeThe determination of the molecular mechanism underlying retinal pathogenesis and visual dysfunction during innate inflammation, and the treatment effect of rapamycin thereon.MethodsThe endotoxin-induced uveitis and retinitis mouse model was established by injecting lipopolysaccharide. The mice were subsequently treated with rapamycin, a mammalian target of rapamycin (mTOR) inhibitor. The rhodopsin mRNA and protein expression level in the retina and the photoreceptor outer segment (OS) length in immunohistochemical stainings were measured, and visual function was recorded by electroretinography. Inflammatory cytokines, their related molecules, mTOR, and LC3 levels were measured by real-time PCR and/or immunoblotting. Leukocyte adhesion during inflammation was analyzed using concanavalin A lectin.ResultsThe post-transcriptional reduction in the visual pigment of rod photoreceptor cells, rhodopsin, OS shortening, and rod photoreceptor cell dysfunction during inflammation were suppressed by rapamycin. Activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and induction of inflammatory cytokines, such as interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), and the activation of the downstream signaling protein, signal transducer and activator of transcription 3 (STAT3), which reduces rhodopsin in the retina during inflammation, were attenuated by rapamycin. Increased leukocyte adhesion was also attenuated by rapamycin. Interestingly, although mTOR activation was observed after NF-κB activation, mTOR inhibition suppressed NF-κB activation at the early phase, indicating that the basal level of activated mTOR was sufficient to activate NF-κB in the retina. In addition, the inhibition of NF-κB suppressed mTOR activation, suggesting a positive feedback loop of mTOR and NF-κB during inflammation. The ratio of LC3II to LC3I, which reflects autophagy induction, was not changed by inflammation but was increased by rapamycin.ConclusionsOur results propose the potential use of rapamycin as a neuroprotective therapy to suppress local activated mTOR levels, related inflammatory molecules, and the subsequent visual dysfunction during retinal inflammation.
Highlights
Recent progress in the medical sciences has shown that inflammation partakes in the pathogenesis of several systemic diseases including arthritis [1], gastrointestinal diseases [2], arteriosclerosis [3], hypertension [4], and metabolic syndrome [5], as well as in neurodegenerative diseases, such as Alzheimer’s disease [6, 7] and diabetic retinopathy [8,9,10,11]
Our results propose the potential use of rapamycin as a neuroprotective therapy to suppress local activated mammalian target of rapamycin (mTOR) levels, related inflammatory molecules, and the subsequent visual dysfunction during retinal inflammation
While mTOR complex 1 (mTORC1) regulates numerous cellular processes including protein synthesis related to growth and differentiation, and plays an important role in cancer therapy, mTORC2 has a regulatory role in the insulin-signaling cascade, which may, be treated by rapamycin [17]
Summary
Recent progress in the medical sciences has shown that inflammation partakes in the pathogenesis of several systemic diseases including arthritis [1], gastrointestinal diseases [2], arteriosclerosis [3], hypertension [4], and metabolic syndrome [5], as well as in neurodegenerative diseases, such as Alzheimer’s disease [6, 7] and diabetic retinopathy [8,9,10,11]. Research into anti-inflammatory treatments as alternatives to the currently used ones, such as steroids, has found rapamycin, a negative regulator of the mammalian target of rapamycin (mTOR) [14], as one of the promising drugs. Rapamycin is currently in global clinical trials for the treatment of the non-infectious ocular inflammatory disease, uveitis [15], and is already a clinically available immunosuppressant [16]. Rapamycin is believed to be a specific inhibitor of mTORC1 [14], a recent study has shown that it can inhibit mTORC2 [17]. While mTORC1 regulates numerous cellular processes including protein synthesis related to growth and differentiation, and plays an important role in cancer therapy, mTORC2 has a regulatory role in the insulin-signaling cascade, which may, be treated by rapamycin [17]
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