G-protein signaling modulator-3, a gene linked to autoimmune diseases, regulates monocyte function and its deficiency protects from inflammatory arthritis.
G-protein signaling modulator-3, a gene linked to autoimmune diseases, regulates monocyte function and its deficiency protects from inflammatory arthritis.
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DOI：
10.1016/j.molimm.2012.12.001
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发表时间：
2013-06
影响因子：
3.6
通讯作者：
Tarrant TK
中科院分区：
文献类型：
--
作者：
Giguère PM;Billard MJ;Laroche G;Buckley BK;Timoshchenko RG;McGinnis MW;Esserman D;Foreman O;Liu P;Siderovski DP;Tarrant TK
GPSM3基因位点的多态性与四种系统性自身免疫性疾病呈负相关，包括类风湿性关节炎和强直性脊柱炎。G蛋白信号调节因子3在髓系细胞中的表达最为明显，它针对趋化因子受体的异源三聚体G蛋白GαI亚单位，对免疫功能至关重要。为了探索GPSM3在单核细胞中的调节作用，在刺激条件下培养人THP-1和原代小鼠髓系细胞；免疫印迹法发现GPSM3在成熟的单核细胞中表达水平最高。为了评价GPSM3缺乏对一种髓系依赖型自身免疫病的影响，在Gpsm3−/−和对照组小鼠中诱导了胶原抗体诱导的关节炎(CAIA)，然后分析了临床评分、足爪肿胀、关节内促炎标志物和组织病理学。缺乏GPSM3的小鼠受到CAIA的保护，Gpsm3−/−小鼠爪部代表单核细胞的促炎性趋化因子受体和细胞因子的表达减少。通过流式细胞仪、细胞凋亡和跨膜趋化实验进一步研究GPSM3缺乏对单核细胞存活率和趋化因子反应性的影响。GPSM3缺陷的髓系细胞在体外减少了向CCL2、CX3CL1和趋化蛋白的迁移，并促进了体外的细胞凋亡。我们的结果表明，GPSM3是单核细胞功能的重要调节因子，涉及分化、存活和趋化机制，而GPSM3表达不足在急性炎症性关节炎中具有保护作用。
Polymorphism at the GPSM3 gene locus is inversely associated with four systemic autoimmune diseases, including rheumatoid arthritis and ankylosing spondylitis. G-protein signaling modulator-3 (GPSM3) expression is most pronounced in myeloid cells, in which it targets heterotrimeric G-protein Gαi subunits of chemokine receptors, critical to immune function. To begin to explore the regulatory role of GPSM3 in monocytes, human THP-1 and primary mouse myeloid cells were cultured under stimulus conditions; GPSM3 was found by immunoblotting to be expressed at highest levels in the mature monocyte. To evaluate the effects of GPSM3 deficiency on a myeloid-dependent autoimmune disease, Collagen Antibody-Induced Arthritis (CAIA) was induced in Gpsm3−/− and control mice, which were then analyzed for clinical score, paw swelling, intra-articular proinflammatory markers, and histopathology. Mice lacking GPSM3 were protected from CAIA, and expression of monocyte-representative pro-inflammatory chemokine receptors and cytokines in paws of Gpsm3−/− mice were decreased. Flow cytometry, apoptosis, and transwell chemotaxis experiments were conducted to further characterize the effect of GPSM3 deficiency on survival and chemokine responsiveness of monocytes. GPSM3-deficient myeloid cells had reduced migration ex vivo to CCL2, CX3CL1, and chemerin and enhanced apoptosis in vitro. Our results suggest that GPSM3 is an important regulator of monocyte function involving mechanisms of differentiation, survival, and chemotaxis, and deficiency in GPSM3 expression is protective in acute inflammatory arthritis.
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