Immunomodulatory functions of TRPM7 and its implications in autoimmune diseases.

An autoimmune disease is an inappropriate response to one's tissues due to a break in immune tolerance and exposure to self-antigens. It often leads to structural and functional damage to organs and systemic disorders. To date, there are no effective interventions to prevent the progression of autoimmune diseases. Hence, there is an urgent need for new treatment targets. TRPM7 is an enzyme-coupled, transient receptor ion channel of the subfamily M that plays a vital role in pathologic and physiologic conditions. While TRPM7 is constitutively activated under certain conditions, it can regulate cell migration, polarization, proliferation and cytokine secretion. However, a growing body of evidence highlights the critical role of TRPM7 in autoimmune diseases, including rheumatoid arthritis, multiple sclerosis and diabetes. Herein, we present (a) a review of the channel kinase properties of TRPM7 and its pharmacological properties, (b) discuss the role of TRPM7 in immune cells (neutrophils, macrophages, lymphocytes and mast cells) and its upstream immunoreactive substances, and (c) highlight TRPM7 as a potential therapeutic target for autoimmune diseases.

Nerve growth factor promotes ASIC1a expression via the NF-κB pathway and enhances acid-induced chondrocyte apoptosis.

Nerve growth factor (NGF) is a neurotrophic factor that is thought to have a broad role in the nervous system and tumors, and has recently been described as a mediator of inflammation. It is not clear whether or not NGF participates in apoptosis of articular chondrocytes. In this study, we determined if NGF affects ASIC1a expression and NF-κB P65 activation in rat chondrocytes, and measured the effectiveness of NGF on apoptotic protein expression in acid-induced chondrocytes. NGF was shown to up-regulate the level of ASIC1a in a dose- and time-dependent fashion. Simultaneously, NGF activated NF-κB P65 in chondrocytes. Additionally, the elevated ASIC1a expression induced by NGF was eliminated by the NF-κB inhibitor (PDTC) in chondrocytes. Moreover, NGF reduced cell viability and induced LDH release under the premise of acid-induced articular chondrocytes. Furthermore, NGF could enhance cleaved-caspase 9 and cleaved-PARP expression in acid-pretreated chondrocytes, and which could be inhibited by using psalmotoxin 1(PcTX1) or PDTC. Together, these results indicated that NGF may up-regulate ASIC1a expression through the NF-κB signaling pathway, and further promote acid-induced apoptosis of chondrocytes.

17ß-estradiol attenuates rat articular chondrocyte injury by targeting ASIC1a-mediated apoptosis.

Epidemiological evidence suggests that the etiology and pathogenesis of rheumatoid arthritis (RA) are closely associated with estrogen metabolism and deficiency. Estrogen protects against articular damage. Estradiol replacement therapy ameliorates local inflammation and knee joint swelling in ovariectomized models of RA. The mechanistic basis for the protective role of 17ß-estradiol (17ß-E2) is poorly understood. Acid-sensing ion channel 1a (ASIC1a), a sodium-permeable channel, plays a pivotal role in acid-induced articular chondrocyte injury. The aims of this study were to evaluate the role of 17ß-E2 in acid-induced chondrocyte injury and to determine the effect of 17ß-E2 on the level and activity of ASIC1a protein. Results showed that pretreatment with 17ß-E2 attenuated acid-induced damage, suppressed apoptosis, and restored mitochondrial function. Further, 17ß-E2 was shown to reduce protein levels of ASIC1a through the ERα receptor, to protect chondrocytes from acid-induced apoptosis, and to induce ASIC1a protein degradation through the autophagy-lysosomal pathway. Taken together, these results show that the use of 17ß-E2 may be a novel strategy for the treatment of RA by reducing cartilage destruction through down-regulation of ASIC1a protein levels.