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BRSK2 in pancreatic β cells promotes hyperinsulinemia-coupled insulin resistance and its genetic variants are associated with human type 2 diabetes

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Journal of Molecular Cell Biology 2023年第5期15卷 21-37页

作者： Rufeng Xu Kaiyuan Wang Zhengjian Yao Yan Zhang Li Jin Jing Pang Yuncai Zhou Kai Wang Dechen liu Yaqin Zhang Peng Sun Fuqiang Wang Xiaoai Chang tengli liu Shusen Wang Yalin Zhang Shuyong Lin Cheng Hu Yunxia Zhu Xiao Han Key Laboratory of Human Functional Genomics of Jiangsu Province Nanjing Medical UniversityNanjing 211166China Institute for Metabolic Disease Fengxian Central Hospital Affiliated to Southern Medical UniversityShanghai 201499China Shanghai Diabetes Institute Shanghai Key Laboratory of Diabetes MellitusShanghai Clinical Center for DiabetesShanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200233China Analysis Center Nanjing Medical UniversityNanjing 210029China Organ Transplant Center Tianjin First Central HospitalNankai UniversityTianjin 300192China State Key Laboratory for Cellular Stress Biology School of Life SciencesXiamen UniversityXiamen 361102China

Brain-specific serine/threonine-protein kinase 2(BRSK2)plays critical roles in insulin secretion andβ-cell ***,whether BRSK2 is associated with human type 2 diabetes mellitus(T2DM)has not been ***,we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese ***2 protein levels are significantly elevated inβcells from T2DM patients and high-fat diet(HFD)-fed mice due to enhanced protein *** with inducibleβ-cell-specific Brsk2 knockout(βKO)exhibit normal metabolism with a high potential for insulin secretion under chow-diet ***,βKO mice are protected from HFD-induced hyperinsulinemia,obesity,insulin resistance,and glucose ***,gain-of-function BRSK2 in matureβcells reversibly triggers hyperglycemia due toβ-cell hypersecretion-coupled insulin ***,BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent *** enhanced basal insulin secretion drives insulin resistance andβ-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 inβ*** findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay betweenβcells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.

关键词： type 2 diabetes mellitus genetic variant BRSK2 β-cell hypersecretion hyperinsulinemia insulin resistance

JNK抑制剂SP600125抑制白细胞介素1β诱导的βTC-6细胞焦亡

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中华内分泌代谢杂志 2023年第5期39卷 430-434页

作者：麻文淼刘腾丽梁瑞刘娜王乐王树森郑荣秀天津医科大学总医院儿科天津300052 南开大学附属第一中心医院卫生健康委员会急救医学重点实验室天津300192

目的研究白细胞介素(IL)-1β是否参与细胞焦亡造成的小鼠胰岛β细胞系βTC-6细胞损伤,以及JNK抑制剂SP600125在抑制IL-1β诱导的βTC-6细胞焦亡中的作用。方法βTC-6细胞系及小鼠胰岛,给予IL-1β孵育48 h,同时给予JNK抑制剂SP600125或I... 详细信息

目的研究白细胞介素(IL)-1β是否参与细胞焦亡造成的小鼠胰岛β细胞系βTC-6细胞损伤,以及JNK抑制剂SP600125在抑制IL-1β诱导的βTC-6细胞焦亡中的作用。方法βTC-6细胞系及小鼠胰岛,给予IL-1β孵育48 h,同时给予JNK抑制剂SP600125或IL-1受体拮抗剂(IL-1Ra)干预,然后通过免疫荧光染色GSDMD和DAPI检测GSDMD表达并观察细胞焦亡形态,实时荧光定量PCR检测细胞焦亡标志基因Gsdmd,IL-1β,IL-18 mRNA表达水平;采用Annexin-V/7-AAD染色结合流式细胞术检测细胞凋亡。结果与对照组相比IL-1β处理组中βTC-6细胞焦亡小体显著增加,焦亡相关基因Gsdmd、IL-1β、IL-18 mRNA表达明显升高(P<0.05),且细胞凋亡增加;经IL-1Ra处理后可有效抑制IL-1β诱导的βTC-6细胞焦亡,提示IL-1β有效的诱导βTC-6细胞焦亡的发生。在IL-1β处理时给予SP600125干预,则抑制细胞焦亡标志物Gsdmd和IL-18 mRNA表达,并且降低细胞凋亡率,说明SP600125抑制IL-1β诱导的βTC-6细胞焦亡。结论细胞焦亡是IL-1β造成的βTC-6细胞损伤的机制之一,而JNK抑制剂SP600125可阻断IL-1β诱导的焦亡途径,具有潜在的抑制βTC-6细胞焦亡的作用。

关键词：细胞焦亡糖尿病 GSDMD 白细胞介素-1β β细胞系

非糖尿病人群中ALDH1A3^(+)INS^(+)细胞与2型糖尿病风险因素的相关性研究

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中华内分泌代谢杂志 2022年第3期38卷 219-224页

作者：刘腾丽梁瑞孙鹏王乐刘娜邹家琦刘尧娟丁雪洁王树森天津市第一中心医院器官移植中心 300192 天津市第一中心医院卫生部危重病急救医学重点实验室 300384

目的探究影响非糖尿病个体β细胞去分化水平的潜在2型糖尿病风险因素。方法通过胰岛素和β细胞去分化标志分子ALDH1A3免疫荧光染色法,检测38名非糖尿病和23例2型糖尿病患者胰腺切片中β细胞去分化水平。对非糖尿病个体胰岛β细胞去分化... 详细信息

目的探究影响非糖尿病个体β细胞去分化水平的潜在2型糖尿病风险因素。方法通过胰岛素和β细胞去分化标志分子ALDH1A3免疫荧光染色法,检测38名非糖尿病和23例2型糖尿病患者胰腺切片中β细胞去分化水平。对非糖尿病个体胰岛β细胞去分化水平与年龄、体重指数、HbA1C、三酰甘油、总胆固醇等临床指标进行相关性分析。结果与非糖尿病个体相比,2型糖尿病患者胰岛内ALDH1A3^(+)INS^(+)细胞比例明显升高(P<0.001)。在糖尿病前期个体胰岛内ALDH1A3^(+)INS^(+)细胞比例降低(P=0.050),且与HbA1C值呈负相关(r=-0.44,P=0.006),但与年龄、体重指数无显著相关性。与血脂指标的相关性分析显示ALDH1A3^(+)INS^(+)细胞百分比与血浆总胆固醇水平呈正相关(r=0.39,P=0.045),但与三酰甘油无相关性。结论ALDH1A3^(+)INS^(+)细胞在糖尿病前期胰岛内显著降低,提示糖尿病前期可能存在β细胞身份的增强以代偿胰岛素分泌需求。ALDH1A3^(+)INS^(+)细胞在血浆总胆固醇水平较高的人群中升高,提示胆固醇可能是诱导β细胞去分化以及造成β细胞损伤的重要因素之一。

关键词：糖尿病 2型 β细胞去分化总胆固醇糖化血红蛋白

IL-27/IL-27R promotes host defense against chlamydial lung infection by suppressing neutrophils recruitment mediated by Th17

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IL-27/IL-27R promotes host defense against chlamydial lung i...

Vγ1+T and Vγ4+T cells mediate majority of γδT cell function during chlamydial airway infection

第十三届全国免疫学学术大会

作者： Xiaoyu zha Gaoju Pang Lida Sun Sai Qiao Wenhao Niu Juyou Liang Lu Tan Hong Zhang tengli liu Huili Zhao Yue Wang Hong Bai Tianjin Medical University

Interleukin-27, a heterodimeric cytokine of IL-12 family, composed of Epstein-Barr virus-induced gene 3(EBI3) and p28, has diverse influences on the immune response. In this study, we identified the role of IL-27/IL-27 R in host defense against Chlamydia lung infection and further investigated the influence of IL-27/IL-27 R on Th1 and Th17 cell responses as well as neutrophils recruitment. Our data showed that mRNA expression of IL-27(EBI3) and IL-27 R(WSX-1) were significantly induced after Cm infection especially on day 7 post-infection(p.i.) in wild type mice. Mice with WSX-1 knockout(WSX-1mice) showed higher severity of the disease with greater body weight loss, more chlamydia growth and more severe inflammatory cell infiltration in lungs compared with WT mice. Th1 cell responses, which played a protective role in Cm infection, was significantly weaken in lungs on day 7 p.i. and day 14 p.i. whereas Th17 cell responses, which can promote neutrophil recruitment, was dramatically enhanced in lungs on day 7 p.i. and day 14 p.i. in WSX-1mice compared with WT mice. Neutrophils in lung were also increased on day 7 p.i. and day 14 p.i. in WSX-1mice compared to WT mice which was in accordant with upregulated mRNA expression of chemokines and cytokines of neutrophils including IL-17, TNFα, IL-6 and CXCR2. To further confirm that severe disease condition in WSX-1mice was caused by increased IL-17 in lungs, we found that WSX-1mice injected with mouse IL-17/IL-17 A-blocking antibody on the day before infection, day 2 p.i. and day 4 p.i. showed improved disease status in the aspects of body weight change, chlamydia growth and neutrophil recruitment in lungs compared to those without IL-17 blocking. Taken together, we concluded that IL-27/IL-27 R plays a protective role in host defense against Chlamydia lung infection by suppressing neutrophils recruitment mediated by Th17.

关键词： Chlamydia Lung infection IL-27/IL-27R Th17 Neutrophil

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Vγ1+T and Vγ4+T cells mediate majority of γδT cell funct...

衣原体呼吸道感染早期IL-17对调节性T细胞及其IL-10分泌的影响

第十二届全国免疫学学术大会

作者： sun lida Pang Gaoju Wang Yue Tang Yingying Qiao Sai Liang Juyou Zhao Huili liu tengli Zheng Ningbo Tan Lu Zhang Yongci Zhang Hong Bai Hong Department of Immunology School of Basic Medical SciencesTianjin Medical UniversityTianjin Key Laboratory of Cellular and Molecular ImmunologyKey Laboratory of Educational Ministry of China

Our previous studies have shown that γδT cells plays an immune protective role against Chlamydial muridarum(Cm)lung infection by producing IFNγ and IL-17 at the early stage of infection and mice deficient in TCRγδ developed more severe disease compared to the wild type(WT) ***,the γδT cells subsets and their functions in immune protection against Cm infection remain ***,We investigate the proliferation,activation and function of lung y8 T cells subsets following Cm lung *** mice were inoculated intranasally with 1×10 inclusion-forming units(IFUs) of Cm to induce the murine Chlamydia *** y8 T cells subsets in lung mononuclear cells were analysed by using flow cytometry and *** cytokine staining was used to detect IFNγ and IL-17 secretion levels by Vγ1T,Vγ4T *** results showed that there are 5 kinds of γδT cell subsets including Vγ1T,Vγ2T,Vγ4T,Vγ5T and Vγ6T cells in lungs of naive *** percentage of each subpopulation shows as Vγ2 > Vγ4 > Vγ1> Vγ6 > Vγ5 in WT ***,Cm lung infection mainly induced Vγ4T cells proliferation in early stage,and then Vγ1T cells became the main γδT cell subsets gradually.Vγ6T also increased after infection and proliferate significantly on 7 th day,however Vγ2T and Vγ5T cells had no significant change in the lung after Cm *** detection showed Vγ1T cells could secrete IFNγ but do not product IL-17,and Cm infection induced IFNγ secretion reached the peak on day 7(p<0.01).Vγ4T cells could secrete both IFNγ and IL-17,and the cytokines levels increased rapidly after Cm infection and reached the peak on day 3(p<0.001).These findings provide in vivo evidence that Vγ4T cells is the major IL-17 and IFNγ-producing γδT cell subsets at the early period of Cm airway infection.

关键词： Chlamydia muridarum γδT cells subsets IL-17 IFNγ

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中华微生物学和免疫学杂志 2018年第11期38卷 807-811页

作者：张虹庞高举查晓宇钮文豪刘腾丽赵慧丽白虹天津医科大学基础医学院免疫学系国家教育部免疫微环境与疾病重点实验室天津市细胞和分子免疫学重点实验室300070

目的探讨IL-17在沙眼衣原体呼吸道感染中对调节性T细胞的影响.方法鼻滴给予野生型(WT,C57BL/6)小鼠和 IL-17-/-小鼠 1×10^3包涵体形成单位(IFU)的鼠型衣原体(Chlamydia muridarum, Cm),构建小鼠衣原体呼吸道感染模型.制备小鼠脾、肺... 详细信息

目的探讨IL-17在沙眼衣原体呼吸道感染中对调节性T细胞的影响.方法鼻滴给予野生型(WT,C57BL/6)小鼠和 IL-17-/-小鼠 1×10^3包涵体形成单位(IFU)的鼠型衣原体(Chlamydia muridarum, Cm),构建小鼠衣原体呼吸道感染模型.制备小鼠脾、肺组织单个核细胞悬液,运用流式细胞术检测调节性T细胞(Treg)百分率;利用RT-PCR技术检测小鼠肺组织中Foxp3和TGF-β的mRNA表达水平;用ELISA方法检测小鼠支气管肺泡灌洗液中IL-10的产生.结果衣原体呼吸道感染第3天,IL-17--小鼠脾、肺组织中的CD4+CD25+T细胞与CD4+CD25+Foxp3+T细胞比例均高于WT小鼠;IL-17-/-小鼠肺组织Foxp3 mRNA表达及支气管肺泡灌洗液中IL-10的分泌显著高于WT小鼠;两种小鼠肺组织TGF-β mRNA表达无显著差异.结论衣原体呼吸道感染早期阶段IL-17可能抑制小鼠调节性T细胞的增殖和IL-10的产生.

关键词：衣原体 Treg IL-17 Th17

An FPS-ZM1-encapsulated zeolitic imidazolate framework as a dual proangiogenic drug delivery system for diabetic wound healing

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Nano Research 2022年第6期15卷 5216-5229页

作者： Yi Sun Bingbo Bao Yu Zhu Junjie Shen Xuanzhe liu Tao Gao Junqing Lin tengli Huang Jia Xu Yimin Chai Xianyou Zheng Department of Orthopedic Surgery Shanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghai 200233China Institute of Microsurgery on Extremities Shanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghai 200233China

Inhibitors that target diabetes pathology-related signaling pathways have great therapeutic potential for diabetic wound ***–organic frameworks(MOFs)are increasingly popular drug delivery systems that have high loading capacity and can release their intrinsic metal ions to act as bioactive *** light of this,a receptor for advanced glycation end products(RAGE)inhibitor,4-chloro-N-cyclohexyl-N-(phenylmethyl)-benzamide(FPS-ZM1),was loaded into a cobalt(Co)-based MOF(zeolitic imidazolate framework-67,ZIF-67)to fabricate FPS-ZM1 encapsulated ZIF-67(FZ@ZIF-67)nanoparticles(NPs).As a result,FZ@ZIF-67 NPs could dually deliver Co ions and FPS-ZM1 in a controlled manner for over 14 *** in vitro study showed that FZ@ZIF-67 NPs not only enhanced angiogenesis by delivering Co ions but also released FPS-ZM1 to promote M2 macrophage polarization and attenuated high glucose(HG)-and/or inflammation-induced impairment of angiogenesis through RAGE ***,in an in vivo study,FZ@ZIF-67 NPs markedly improved re-epithelialization,collagen deposition,neovascularization,and relieved inflammation in diabetic wounds in *** study not only provides a low-cost,effective,and synergistic proangiogenic bioactive agent but also demonstrates that targeting diabetes-related pathological signaling pathways is necessary to ameliorate vascularization impairment during diabetic wound healing.

关键词： zeolitic imidazolate framework-67 drug delivery dual-controlled release angiogenesis diabetic wound

沙眼衣原体小鼠肺炎株呼吸道感染诱导肺组织中性粒细胞浸润及活化

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中华微生物学和免疫学杂志 2014年第12期34卷 891-896页

作者：唐莹莹乔赛赵慧丽王悦刘腾丽邢冬红张永慈白虹天津医科大学基础医学院免疫学教研室天津市细胞和分子免疫学重点实验室国家教育部免疫微环境与疾病重点实验室300070

目的：探讨小鼠沙眼衣原体肺炎感染中中性粒细胞（ polymorphonuclear neutrophils， PMN）的募集、活化及诱导其趋化的免疫学机制。方法 C57BL/6（C57）小鼠鼻腔吸入3×10^3 IFU（in-clusion-forming units）沙眼衣原体小鼠肺炎株（Chl... 详细信息

目的：探讨小鼠沙眼衣原体肺炎感染中中性粒细胞（ polymorphonuclear neutrophils， PMN）的募集、活化及诱导其趋化的免疫学机制。方法 C57BL/6（C57）小鼠鼻腔吸入3×10^3 IFU（in-clusion-forming units）沙眼衣原体小鼠肺炎株（Chlamydia muridarum，Cm）建立小鼠沙眼衣原体肺炎模型。取感染后不同时间点小鼠肺组织进行组织病理学染色；通过检测肺组织内髓过氧化物酶（ myelo-peroxidase，MPO）的含量，检测 PMN 在肺组织聚集；分离小鼠肺组织单个核细胞，Giemsaˊs 染色计数肺组织炎症细胞种类；流式细胞术检测 CD11b^＋ Gr1^＋ PMN 细胞百分率及 CD11b^＋ PMN 活性水平；应用RT-PCR 技术检测 Cm 感染后肺组织内与 PMN 募集相关的趋化性细胞因子（MIP-2、LIX、KC、MCP-1）的表达，探讨小鼠 Cm 呼吸道感染过程中 PMN 趋化机制。结果一定剂量的 Cm 呼吸道吸入诱导C57小鼠衣原体肺炎，与对照组（感染第0天）比较，肺组织内有大量炎性细胞浸润，主要包括 PMN、单核细胞、淋巴细胞，其中 PMN 在肺内的聚集早于单核细胞；Cm 感染诱导小鼠肺组织 MPO 含量升高，在感染第7天达到高峰，第14天虽然有所下降，但仍明显高于对照组；流式结果显示，Cm感染后，CD11b^＋Gr1^＋细胞百分比、PMN 总数均显著高于对照组，同时 PMN CD11b 分子的表达在感染后也显著升高，说明 Cm 感染能诱导小鼠肺组织内 PMN 大量聚集并活化。RT-PCR 结果显示，Cm 感染后小鼠肺组织内与 PMN 募集相关的趋化性细胞因子（MIP-2、LIX、KC、MCP-1）的含量明显升高，提示Cm感染上调 PMN 相关趋化性细胞因子的表达，从而吸引大量 PMN 在肺部聚集参与炎症反应。结论一定剂量的 Cm 可以诱导感染小鼠肺组织内 PMN 相关趋化性细胞因子的分泌，从而使 PMN 在肺组织内大量浸润并活化，在抵抗衣原体感染中发挥重要作用。

关键词：沙眼衣原体肺炎中性粒细胞趋化性细胞因子

产生IL-17的γδT细胞在沙眼衣原体呼吸道感染早期促进中性粒细胞的募集

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中华微生物学和免疫学杂志 2017年第1期37卷 1-5页

作者：梁聚友孙丽妲庞高举王悦乔赛檀露张虹唐莹莹刘腾丽赵慧丽白虹天津医科大学基础医学院免疫学系、国家教育部免疫微环境与疾病重点实验室、天津市细胞和分子免疫学重点实验室 300070

目的探讨沙眼衣原体呼吸道感染早期产生IL-17的γδT细胞对中性粒细胞募集的影响及其机制。方法WT（C57BL/6）与TCRδ－/－小鼠鼻腔吸入3×103 IFU（inclusion-forming units）沙眼衣原体小鼠肺炎菌株（Chlamydia muridarum, Cm），建... 详细信息

目的探讨沙眼衣原体呼吸道感染早期产生IL-17的γδT细胞对中性粒细胞募集的影响及其机制。方法WT（C57BL/6）与TCRδ－/－小鼠鼻腔吸入3×103 IFU（inclusion-forming units）沙眼衣原体小鼠肺炎菌株（Chlamydia muridarum, Cm），建立沙眼衣原体小鼠肺炎模型。分离感染不同时间点小鼠肺组织单个核细胞，流式细胞术检测肺组织CD11b＋Gr1＋中性粒细胞（PMN）百分率；细胞内因子染色检测γδT细胞IL-17的合成；RT-PCR检测小鼠肺组织IL-17及KC（中性粒细胞趋化因子）、IL-6 mRNA表达。结果一定剂量的Cm呼吸道感染诱导小鼠肺组织γδT细胞分泌大量IL-17，与未感染组比较，感染后第3天小鼠肺组织CD3＋ γδT＋细胞分泌的IL-17显著增加（P〈0.001），并且持续到感染的第7天（P〈0.05）；TCRδ－/－小鼠Cm呼吸道感染后第3天肺组织IL-17 mRNA的表达以及PMN百分率显著低于WT鼠；进一步研究显示TCRδ－/－小鼠在感染后第3天及第7天中性粒细胞趋化因子KC和IL-6在小鼠肺组织的表达显著降低。结论产生大量IL-17的γδT细胞可能通过上调KC和IL-6的表达在沙眼衣原体呼吸道感染中发挥PMN募集作用。

关键词：沙眼衣原体肺炎菌株中性粒细胞 γδT细胞 IL-17