Immunology and Cell Biology (2015), 1–9 & 2015 Australasian Society for Immunology Inc. All rights reserved 0818-9641/15 www.nature.com/icb

ORIGINAL ARTICLE

Gαq controls rheumatoid arthritis via regulation of Th17 differentiation Yuan Liu1,4, Dashan Wang2,4, Fang Li3 and Guixiu Shi1 Gαq, the α-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 Gαq 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 Gαq negatively controls the disease activity of RA. However, how Gαq 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 Gαq in control of Th17 differentiation. We investigated the relationship between Gαq and Th17 in RA patients. We then investigated the mechanism of how Gαq regulated Th17 differentiation by using Gnaq − / − mice. We observed that the expression of Gαq was negatively associated with interleukin-17A expression in RA patients, indicating that Gαq negatively controlled the differentiation of Th17 cells. By using Gnaq − / − mice, we demonstrated that Gαq 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 RORα (RAR-related orphan receptor-α). These data suggest the possibility of targeting Gαq to develop a novel therapeutic regimen for autoimmune disease. Immunology and Cell Biology advance online publication, 3 March 2015; doi:10.1038/icb.2015.13

Gαq is the α-subunit of Gq protein that is encoded by GNAQ. Gq protein is one of the subfamilies of the heterotrimeric G proteins. The heterotrimeric G proteins consist of a α-subunit that binds and hydrolyses guanosine-5′-triphosphate as well as a β- and a γ-subunit that form an undissociable complex. Based on the types of their α-subunits, G proteins can be grouped into four subfamilies, Gαi, Gαs, Gαq/11 and G12/13, and each subfamily contents several members of G proteins. Gq protein is a member of the Gαq/11 subfamily.1 Gαq is ubiquitously expressed in mammalian cells including hematopoietic cells and couples a huge variety of receptors to channel proteins, enzymes and other effector molecules.2–4 The Gαq containing G protein initially attracted our attention for its physiological significance in cardiovascular system in the 1990s.5,6 Increased expression level of Gαq is associated with changes in cardiomyocyte survival and in the development of cardiac disease in patients.7,8 In recent years, studies have also indicated the important roles of Gαq in regulating both innate and adaptive immunity, providing a new insight into the mechanism of immune regulation and autoimmune disease.9,10 Rheumatoid arthritis (RA) is a common autoimmune disease characterized by persistent synovial inflammation, destruction of joint

cartilage and bone and autoantibodies, resulting in progressive disability, systemic complications, early death and socioeconomic costs. The etiology of RA is still not fully understood.11 A previous study showed that Gnaq − / − bone marrow chimeric mice developed autoimmunity with multiorgan involvement and joints swelling, indicating that Gαq may play a role in the pathogenesis of RA.10 Further study in RA patients found that Gαq expression level was significantly decreased in RA patients compared with healthy individuals. The expression level of Gαq mRNA in peripheral blood lymphocytes from RA patients was correlated with RA disease activity (DAS28), anti-cyclic citrullinated protein antibodies, C-reactive protein and rheumatoid factor.12 These data ensure the role of Gαq in the pathogenesis of RA. However, how is Gαq involved in the pathogenesis of RA is still not clear. T helper type 17 (Th17) is a new subset of effector T helper cells that is different from Th1 and Th2. Th17 can produce interleukin (IL)-17A, IL-17F, IL-21, IL-22 and granulocyte-macrophage colonystimulating factor (GM-CSF).13 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.14,15

1 Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital, Xiamen University, Xiamen, China; 2Molecular Biology Research Center, Shandong Medical College, Linyi, China and 3Department of Endocrinology and Metabolism, The Third People’s Hospital of Chengdu and The Second Affiliated Clinical College of Chengdu of Chongqing Medical University, Chengdu, China 4These authors contributed equally to this work. Correspondence: Dr G Shi, Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital, Xiamen University, No. 55, Zhenhai Road, Xiamen 361003, China. E-mail: [email protected] Received 9 May 2014; revised 19 January 2015; accepted 19 January 2015

Gαq controls RA via regulation of Th17 Y Liu et al 2

RESULTS Expression level of Gαq and IL-17A was negatively related in RA patients Our previous study found that Gαq expression level was significantly decreased in RA patients, and the expression level of Gαq mRNA was negatively correlated with RA disease activity.12 These data suggested a negative role of Gαq in the pathogenesis of RA. Th17 is the main effector cell in the pathogenesis of RA, and whether Gαq is involved in the regulation of Th17 and has further participated in the pathogenesis of RA raised our interests. We first investigated the association of Gαq and IL-17A mRNA expression level in 20 RA patients (Figure 1a). We then investigated the association of Gαq mRNA expression level and IL-17A protein level in the serum in both RA (Figure 1b) and ankylosing spondylitis patients (Figure 1c). Our result showed that the expression level of Gαq and IL-17A was negatively related. These data suggest that Gαq might negatively regulate Th17 differentiation.

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Gαq controls rheumatoid arthritis via regulation of Th17 differentiation.

Gαq, the α-subunit of Gq protein, is ubiquitously expressed in mammalian cells. It initially attracted attention for its physiological significance in...
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