Drug Design, Development and Therapy (Jul 2020)
Loratadine Alleviates Advanced Glycation End Product-Induced Activation of NLRP3 Inflammasome in Human Chondrocytes
Abstract
Feng Gao,1 Shanyong Zhang2 1Department of Orthopedics, The Second Hospital of Jilin University, Changchun City, Jilin Province 130041, People’s Republic of China; 2Department of Spine Surgery, The Second Hospital of Jilin University, Changchun City, Jilin Province 130041, People’s Republic of ChinaCorrespondence: Shanyong ZhangDepartment of Spine Surgery, The Second Hospital of Jilin University, No. 218, Zi Qiang Street, Changchun City, Jilin Province 130041, People’s Republic of ChinaTel +86-431-81136890Fax +86-431-81136993Email [email protected]: Chondrocytes in joint tissue are responsible for the synthesis and degradation of the cartilage matrix. Chondrocytes have been closely linked to the pathogenesis of osteoarthritis and cartilage damage. Targeted drug intervention directed at chondrocyte function is a promising strategy for the treatment of osteoarthritis. The effects of histamine receptor H1 (H1R) and its antagonist loratadine in osteoarthritic chondrocytes are less known.Materials and Methods: The inhibitory effects of loratadine on NLRP3 inflammasome and the NADPH oxidase subunit NOX4 were assessed in advanced glycation end products (AGEs)-treated SW1353 chondrocytes by real-time PCR, ELISA, and Western blot experiments. The mitochondrial ROS level was measured using the specific probe MitoSOX Red. The dependent effect of loratadine on the transcriptional factor nuclear factor erythroid 2-related factor 2 (NRF2) was evaluated through an oligo-based siRNA knockdown approach and Western blot analysis.Results: The expression of H1R was dose-responsively induced by AGEs in chondrocytes. Treatment with loratadine mitigated AGEs-induced oxidative stress, as revealed by suppressed production of mitochondrial ROS and the NADPH oxidase subunit NOX4. Loratadine treatment inhibited the expression of TxNIP and several components of the NLRP3 inflammasome complex, including NLRP3, ASC, and cleaved caspase 1 (P10). Moreover, loratadine suppressed the expression of NRF2, and the silencing of NRF2 abolished the suppressive effect of loratadine on NLRP3 inflammasome activation.Conclusion: Our study demonstrates that loratadine protects chondrocytes from AGEs-induced TxNIP/NLRP3 inflammasome activation by modulating the expression of the transcriptional factor NRF2. This finding implies that loratadine has therapeutic potential in the treatment of osteoarthritis and cartilage injury.Keywords: histamine H1 receptor, loratadine, NLRP3 inflammasome, NRF2, chondrocyte
