A novel GRK2 inhibitor alleviates experimental arthritis through restraining Th17 cell differentiation

被引：8

作者：

Tao, Juan ^{[1
,2
]}

Jiang, Chunru ^{[1
]}

Guo, Paipai ^{[1
]}

Chen, Huijuan ^{[1
]}

Zhu, Zhenduo ^{[1
]}

Su, Tiantian ^{[1
]}

Zhou, Weijie ^{[1
]}

Tai, Yu ^{[1
]}

Han, Chenchen ^{[1
]}

Ma, Yang ^{[1
]}

Chen, Jingyu ^{[1
]}

Sun, Wuyi ^{[1
]}

Wang, Yuanyuan ^{[2
]}

Wei, Wei ^{[1
,4
]}

Wang, Qingtong ^{[1
,3
,4
]}

机构：

[1] Anhui Med Univ, Key Lab Antiinflammatory & Immune Med, Anhui Collaborat Innovat Ctr Antiinflammatory & Im, Inst Clin Pharmacol,Minist Educ, Hefei 230032, Peoples R China

[2] Anhui Med Univ, Dept Pharm, Hosp 2, Hefei 230032, Anhui, Peoples R China

[3] Anhui Med Univ, Peoples Hosp Hefei 1, Affiliated Hosp 3, Hefei 230061, Peoples R China

[4] Anhui Med Univ, Affiliated Hosp 3, Inst Clin Pharmacol, Hefei, Anhui, Peoples R China

来源：

BIOMEDICINE & PHARMACOTHERAPY | 2023年 / 157卷

基金：

中国国家自然科学基金;

关键词：

Paeoniflorin-6?-O-benzene sulfonate; G protein coupled receptor 2; -arrestin2; Th17; Rheumatoid arthritis; ADJUVANT-INDUCED ARTHRITIS; ACTIVATION; RECEPTOR; INFLAMMATION; PROGRESSION; ADENOSINE; ANGIOGENESIS; PATHOGENESIS; SUPPRESSES; INCREASES;

D O I：

10.1016/j.biopha.2022.113997

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

T helper type 17 (Th17) cell which is induced by interleukine-6 (IL-6)-signal transducers and activators of transcription 3 (STAT3) signaling is a central pro-inflammatory T cell subtype in rheumatoid arthritis (RA) and could be significantly reduced by paeoniflorin-6 '-O-benzene sulfonate (CP-25) treatment with unclear mecha-nisms. This study was aimed to found out the mechanism of CP-25 in hampering Th17 cells differentiation in arthritic animals thus explore more therapeutic targets for RA. In mice with collagen-induced arthritis (CIA), both circulating and splenic Th17 subsets were expanded with increased STAT3 phosphorylation and decreased Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1)-beta-arrestin2 (arrb2)-STAT3 interaction in CD4+ helper T (Th) cells. Either CP-25 or paroxetine (PAR), an established G protein coupled receptor kinase 2 (GRK2) inhibitor treatment effectively relieved the joints inflammation of CIA mice with substantially reduced Th17 cell population through inhibiting STAT3 and restoring the SHP1-arrb2-STAT3 complex. Knockout of arrb2 exacerbated the clinical manifestations of collagen antibody-induced arthritis with upregulated Th17 cells. In vitro studies revealed that depletion of arrb2 or inhibition of SHP1 promoted Th17 cell differentiation. Moreover, stimulation of adenosine A3 receptor (A3AR) simultaneously promoted Th17 cell differentiation via accelerating abbr2-A3AR binding, which could be prevented through inhibiting GRK2 phosphorylation by CP-25 or PAR, or genetically reducing GRK2. This work has demonstrated that CP-25 or PAR treatment recovers the SHP1-arrb2-STAT3 complex which prevents STAT3 activation in Th cells through reducing arrb2 recruitment to A3AR by inhibiting GRK2 phosphorylation, leading to the reduction in Th17 cell differentiation and arthritis attenuation.

引用

页数：15