Gαq controls rheumatoid arthritis via regulation of Th17 differentiation

G alpha q, the alpha-subunit of Gq protein, is ubiquitously expressed in mammalian cells. It initially attracted attention for its physiological significance in cardiovascular system. In recent years, studies have also indicated the important roles of G alpha q in regulating immunity, supplying us a new insight into the mechanism of immune regulation. T helper type 17 (Th17) cells are potent inducers of tissue inflammation. Many studies have shown that Th17 cells are major effector cells in the pathogenesis of many experimental autoimmune diseases and human inflammatory conditions such as rheumatoid arthritis (RA). One of our previous studies has shown that G alpha q negatively controls the disease activity of RA. However, how G alpha q controls the pathogenesis of autoimmune disease is not clear. Whether this effect is via the regulation of Th17 differentiation is still not known. We aimed to find out the role of G alpha q in control of Th17 differentiation. We investigated the relationship between G alpha q and Th17 in RA patients. We then investigated the mechanism of how G alpha q regulated Th17 differentiation by using Gnaq(-/-) mice. We observed that the expression of G alpha q was negatively associated with interleukin-17A expression in RA patients, indicating that G alpha q negatively controlled the differentiation of Th17 cells. By using Gnaq(-/-) mice, we demonstrated that Gaq inhibited the differentiation of Th17 cell via regulating the activity of extracellular signal-regulated kinase-1/2 to control the expression of STAT3 (signal transducer and activator of transcription 3) and ROR alpha (RAR-related orphan receptor-alpha). These data suggest the possibility of targeting G alpha q to develop a novel therapeutic regimen for autoimmune disease.