MD2 blockade prevents modified LDL-induced retinal injury in diabetes by suppressing NADPH oxidase-4 interaction with Toll-like receptor-4

Chen Huaicheng; Yan Tao; Song Zongming; Ying Shilong; Wu Beibei; Ju Xin; Yang Xi; Qu Jia; Wu Wencan; Zhang Zongduan; Wang Yi

doi:10.1038/s12276-021-00607-w

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자료유형: 학술저널

저자정보: Chen Huaicheng (Wenzhou Medical University) Yan Tao (Wenzhou Medical University) Song Zongming (Wenzhou Medical University) Ying Shilong (Wenzhou Medical University) Wu Beibei (Wenzhou Medical University) Ju Xin (Wenzhou Medical University) Yang Xi (Wenzhou Medical University) Qu Jia (Wenzhou Medical University) Wu Wencan (Wenzhou Medical University) Zhang Zongduan (Wenzhou Medical University) Wang Yi (Wenzhou Medical University)

저널정보: 대한생화학·분자생물학회 Experimental and Molecular Medicine Experimental and Molecular Medicine 제53권

발행연도: 2021.4

수록면: 1 - 14 (14page)

DOI: 10.1038/s12276-021-00607-w

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Modified LDL-induced inflammation and oxidative stress are involved in the pathogenesis of diabetic retinopathy. Recent studies have also shown that modified LDL activates Toll-like receptor 4 (TLR4) to mediate retinal injury. However, the mechanism by which modified LDL activates TLR4 and the potential role of the TLR4 coreceptor myeloid differentiation protein 2 (MD2) are not known. In this study, we inhibited MD2 with the chalcone derivatives L2H17 and L6H21 and showed that MD2 blockade protected retinal Muller cells against highly oxidized glycated-LDL (HOG-LDL)-induced oxidative stress, inflammation, and apoptosis. MD2 inhibition reduced oxidative stress by suppressing NADPH oxidase-4 (NOX4). Importantly, HOG-LDL activated TLR4 and increased the interaction between NOX4 and TLR4. MD2 was required for the activation of these pathways, as inhibiting MD2 prevented the association of NOX4 with TLR4 and reduced NOX4-mediated reactive oxygen species production and TLR4-mediated inflammatory factor production. Furthermore, treatment of diabetic mice with L2H17 significantly reduced LDL extravasation in the retina and prevented retinal dysfunction and apoptosis by suppressing the TLR4/MD2 pathway. Our findings provide evidence that MD2 plays a critical role in mediating modified LDL-induced cell injury in the retina and suggest that targeting MD2 may be a potential therapeutic strategy.

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