The role of Ca2+ in acid-sensing ion channel 1a-mediated chondrocyte pyroptosis in rat adjuvant arthritis

• Published in: Laboratory investigation 2019-04, Vol.99 (4), p.499-513
• Main Authors: Wu, Xiaoshan, Ren, Guiling, Zhou, Renpeng, Ge, Jinfang, Chen, Fei-Hu
• Format: Article
• Language: English
• Subjects: 13/21; 13/51; 13/89; 14/1; 42/34; 45/77; 631/250/256/2177; 692/699/1670/498; 82/80; 96/21; Acidity; Acidosis; Amiloride; Apoptosis; Arthritis; Autoimmune diseases; Calcium (intracellular); Calcium ions; Calcium permeability; Cartilage; Caspase; Caspase-1; Cell death; Chondrocytes; Cytokines; IL-1β; Inflammasomes; Inflammation; Interleukin 18; Interleukins; Ion channels; Joint diseases; L-Lactate dehydrogenase; Laboratory Medicine; Lactate dehydrogenase; Lactic acid; Medicine; Medicine & Public Health; Pathology; Proteins; Pyroptosis; Rheumatoid arthritis; Rodents; Sodium channels
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/s41374-018-0135-3

Rheumatoid arthritis is an autoimmune disease with a poor prognosis. Pyroptosis is a type of proinflammatory programmed cell death that is characterised by the activation of caspase-1 and secretion of the proinflammatory cytokines interleukin (IL)-1β/18. Previous reports have shown that pyroptosis is closely related to the development of some autoimmune diseases, such as rheumatoid arthritis. The decrease in the pH of joint fluid is a main pathogenic feature of RA and leads to excessive apoptosis in chondrocytes. Acid-sensitive ion channels (ASICs) are extracellular H+-activated cation channels that mainly influence Na+ and Ca2+ permeability. In this study, we investigated the role of Ca2+ in acid-sensing ion channel 1a-mediated chondrocyte pyroptosis in an adjuvant arthritis rat model. The expression of apoptosis-associated speck-like protein, NLRP3, caspase-1, ASIC 1a, IL-1β and IL-18 was upregulated in the joints of rats compared with that in normal rats, but the expression of Col2a in cartilage was decreased. However, these changes were reversed by amiloride, which is an inhibitor of ASIC1a. Extracellular acidosis significantly increased the expression of ASIC1a, IL-1β, IL-18, ASC, NLRP3 and caspase-1 and promoted the release of lactate dehydrogenase. Interestingly, Psalmotoxin-1 (Pctx-1) and BAPTA-AM inhibited these effects. These results indicate that ASIC1a mediates pyroptosis in chondrocytes from AA rats. The underlying mechanism may be associated with the ability of ASIC1a to promote [Ca2+]i and upregulate the expression of the NLRP3 inflammasome.