NLRP3 Attenuates Intraocular Inflammation by Inhibiting AIM2-Mediated Pyroptosis Through the Phosphorylated Salt-Inducible Kinase 1/Sterol Regulatory Element Binding Transcription Factor 1 Pathway

作者全名："Meng, Jiayu; Li, Na; Liu, Xianyang; Qiao, Shengjun; Zhou, Qian; Tan, Jun; Zhang, Ting; Dong, Zhifang; Qi, Xiaopeng; Kijlstra, Aize; Mao, Liming; Yang, Peizeng; Hou, Shengping"

作者地址："[Meng, Jiayu; Liu, Xianyang; Zhou, Qian; Tan, Jun; Yang, Peizeng; Hou, Shengping] Chongqing Med Univ, Affiliated Hosp 1, Chongqing Eye Inst, Chongqing Key Lab Ophthalmol, Chongqing, Peoples R China; [Meng, Jiayu; Liu, Xianyang; Zhou, Qian; Tan, Jun; Yang, Peizeng; Hou, Shengping] Chongqing Med Univ, Affiliated Hosp 1, Natl Clin Res Ctr Ocular Dis, Chongqing Branch,Municipal Div, Chongqing, Peoples R China; [Li, Na] Chongqing Med Univ, Coll Basic Med, Chongqing, Peoples R China; [Qiao, Shengjun; Qi, Xiaopeng] Shandong Univ, Qilu Hosp, Adv Med Res Inst, Cheeloo Coll Med,Key Lab Expt Teratol,Minist Educ, Jinan, Shandong, Peoples R China; [Zhang, Ting; Kijlstra, Aize] Chinese Acad Sci, Shenzhen Inst Adv Technol, Shenzhen, Peoples R China; [Dong, Zhifang] Chongqing Med Univ, Childrens Hosp, Chongqing Key Lab Translat Med Res Cognit Dev & Le, Chongqing, Peoples R China; [Mao, Liming] Nantong Univ, Sch Med, Dept Immunol, Nantong, Jiangsu, Peoples R China"

通信作者："Yang, PZ; Hou, SP (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Chongqing Eye Inst, Chongqing Key Lab Ophthalmol, Chongqing, Peoples R China.; Yang, PZ; Hou, SP (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Natl Clin Res Ctr Ocular Dis, Chongqing Branch,Municipal Div, Chongqing, Peoples R China."

来源：ARTHRITIS & RHEUMATOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000940335800001

JCR分区：Q1

影响因子：11.4

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：　

摘要："Objective. The NLRP3 inflammasome has been shown to be involved in the development of uveitis, but the exact mechanism remains elusive. This study was undertaken to explore the role of NLRP3 in the development of uveitis.Methods. First, Nlrp3-deficient mice were used to study the role of NLRP3 in experimental autoimmune diseases, such as experimental autoimmune uveitis (EAU) and experimental autoimmune encephalomyelitis (EAE). Next, the gathering of ASC, activation of caspase 1 and gasdermin D, and secretion of lactate dehydrogenase and interleukin-1 beta were detected to confirm macrophage pyroptosis and AIM2 activation in the Nlrp3(-/-) mice. Additionally, RNA sequencing and chromatin immunoprecipitation-polymerase chain reaction were used to investigate the phosphorylated salt-inducible kinase 1 (p-SIK1)/sterol regulatory element binding transcription factor 1 (SREBF1) pathway, which regulates the transcription of Aim2. Finally, overexpression of Nlrp3 was applied to treat EAU.Results. Surprisingly, our findings show that NLRP3 plays an antiinflammatory role in 2 models of EAU and EAE. Additionally, macrophages show an increased M1 activation and pyroptosis in Nlrp3(-/-) mice. Further experiments indicate that this pyroptosis of macrophages was mediated by the up-regulated transcription of Aim2 as a result of Nlrp3 deficiency. In mechanistic studies, Nlrp3 deficiency was implicated in the down-regulation of p-SIK1 and subsequently the up-regulation of SREBF1, which binds to Aim2 and then promotes the latter's transcription. Finally, Aim2 deficiency, RNA silencing of Aim2 or Srebf1, and overexpression of Nlrp3 resulted in attenuated inflammation of EAU.Conclusion. Our data demonstrate that NLRP3 inhibits AIM2 inflammasome-mediated EAU by regulating the p-SIK1/SREBF1 pathway, highlighting the therapeutic potential of targeting Nlrp3."

基金机构："National Natural Science Foundation Project of China [81873678, 82070951, 82271078, 32070919, 31700893]; Innovative Research Group Project of Chongqing Education Commission [CXQT19015]; Natural Science Foundation Project of Chongqing [cstc2019jcyjmsxmX0120]; Innovation Supporting Plan of Overseas Study of Chongqing [cx2018010]; National Key Clinical Specialties Construction Program of China; Chongqing Branch of National Clinical Research Center for Ocular Diseases; Chongqing Key Laboratory of Ophthalmology (award CSTC) [2008CA5003]; Natural Science Foundation Project of Chongqing Medical University [W0047]; Natural Science Foundation of Jiangsu province [BK20201442]"

基金资助正文："Supported by National Natural Science Foundation Project of China (awards 81873678, 82070951, 82271078, 32070919, and 31700893), The Innovative Research Group Project of Chongqing Education Commission (award CXQT19015), Natural Science Foundation Project of Chongqing (award cstc2019jcyjmsxmX0120), the Innovation Supporting Plan of Overseas Study of Chongqing (award cx2018010) and National Key Clinical Specialties Construction Program of China, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing Key Laboratory of Ophthalmology (award CSTC, 2008CA5003), Natural Science Foundation Project of Chongqing Medical University (award W0047), and Natural Science Foundation of Jiangsu province (award BK20201442)."