Deficiency ofβ-arrestin2 exacerbates inflammatory arthritis by facilitating plasma cell formation  

作　　者：Wei-jie Zhou Dan-dan Wang Juan Tao Yu Tai Zheng-wei Zhou Zhen Wang Pai-pai Guo Wu-yi Sun Jing-yu Chen Hua-xun Wu Shang-xue Yan Ling-ling Zhang Qing-tong Wang Wei Wei 

机构地区：[1]Institute of Clinical Pharmacology,Anhui Medical University,Key Laboratory of Anti-Inflammatory and Immune Medicine,Ministry of Education,Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine,Hefei,230032,China

出　　处：《Acta Pharmacologica Sinica》2021年第5期755-766,共12页中国药理学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(81202541,81973332,81973314);the Anhui Provincial Natural Science Foundation for Distinguished Young Scholars(1808085J28);the Key Projects of Natural Science Research of Anhui Colleges and Universities(KJ2017A176);Anhui University Excellent Youth Talent Support Program(gxyqZD2017025);Innovation and Entrepreneurship Support Program for Returnees of Anhui Province,the Foundation for Young Academic Backbone of Anhui Medical University,and the Grants for Young Talents of Anhui Medical University(2013).

摘　　要：β-arrestin2(β-arr2)is,a key protein that mediates desensitization and internalization of G protein-coupled receptors and participates in inflammatory and immune responses.Deficiency ofβ-arr2 has been found to exacerbate collagen antibody-induced arthritis(CAIA)through unclear mechanisms.In this study we tried to elucidate the molecular mechanisms underlyingβ-arr2 depletion-induced exacerbation of CAIA.CAIA was induced inβ-arr2−/−and wild-type(WT)mice by injection of collagen antibodies and LPS.The mice were sacrificed on d 13 after the injection,spleen,thymus and left ankle joints were collected for analysis.Arthritis index(AI)was evaluated every day or every 2 days.We showed thatβ-arr2−/−mice with CAIA had a further increase in the percentage of plasma cells in spleen as compared with WT mice with CAIA,which was in accordance with elevated serum IgG1 and IgG2A expression and aggravating clinical performances,pathologic changes in joints and spleen,joint effusion,and joint blood flow.Both LPS stimulation of isolated B lymphocytes in vitro and TNP-LPS challenge in vivo led to significantly higher plasma cell formation and antibodies production inβ-arr2−/−mice as compared with WT mice.LPS treatment induced membrane distribution of toll-like receptor 4(TLR4)on B lymphocytes,accordingly promoted the nuclear translocation of NF-κB and the transcription of Blimp1.Immunofluorescence analysis confirmed that more TLR4 colocalized withβ-arr2 in B lymphocytes in response to LPS stimulation.Depletion ofβ-arr2 restrained TLR4 on B lymphocyte membrane after LPS treatment and further enhanced downstream NF-κB signaling leading to additional increment in plasma cell formation.In summary,β-arr2 depletion exacerbates CAIA and further increases plasma cell differentiation and antibody production through inhibiting TLR4 endocytosis and aggravating NF-κB signaling.

关 键 词：rheumatoid arthritis β-arrestin2 TLR4 plasma cell B lymphocytes LPS 

分 类 号：R96[医药卫生—药理学] R68[医药卫生—药学]