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METTL14 downregulation drives S100A4^(+)monocyte-derived macrophages via myd88/NF-κB pathway to promote MAFLD progression

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2176-2192页

作者： Yue-fan Wang Wen-li Zhang Zhi-xuan Li Yue Liu Jian Tan Hao-zan Yin Zhi-chao Zhang Xian-jie Piao Min-hao Ruan Zhi-hui Dai Si-jie Wang Chen-yang Mu Ji-hang Yuan Shu-han Sun Hui Liu Fu Yang The Third Department of Hepatic Surgery Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University200438 ShanghaiChina The Department of Medical Genetics Naval Medical University200433 ShanghaiChina Translational Medicine Research Center Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital100048 BeijingChina The Department of Pharmaceutical Analysis School of PharmacyNaval Medical University200433 ShanghaiChina Key Laboratory of Biosafety Defense Ministry of Education200433 ShanghaiChina Shanghai Key Laboratory of Medical Biodefense 200433 ShanghaiChina

Without intervention,a considerable proportion of patients with metabolism‐associated fatty liver disease(MAFLD)will progress from simple steatosis to metabolism‐associated steatohepatitis(MASH),liver fibrosis,and even hepatocellular carcinoma.However,the molecular mechanisms that control progressive MAFLD have yet to be fully determined.Here,we unraveled that the expression of the N6-methyladenosine(m6A)methyltransferase METTL14 is remarkably downregulated in the livers of both patients and several murine models of MAFLD,whereas hepatocyte-specific depletion of this methyltransferase aggravated lipid accumulation,liver injury,and fibrosis.Conversely,hepatic Mettl14 overexpression alleviated the above pathophysiological changes in mice fed on a high-fat diet(HFD).Notably,in vivo and in vitro mechanistic studies indicated that METTL14 downregulation decreased the level of GLS2 by affecting the translation efficiency mediated by YTHDF1 in an m6A-depedent manner,which might help to form an oxidative stress microenvironment and accordingly recruit Cx3cr1^(+)Ccr2^(+)monocyte-derived macrophages(Mo-macs).In detail,Cx3cr1^(+)Ccr2^(+)Mo-macs can be categorized into M1-like macrophages and S100A4-positive macrophages and then further activate hepatic stellate cells(HSCs)to promote liver fibrosis.Further experiments revealed that CX3CR1 can activate the transcription of S100A4 via CX3CR1/myd88/NF-κB signaling pathway in Cx3cr1^(+)Ccr2^(+)Mo-macs.Restoration of METTL14 or GLS2,or interfering with this signal transduction pathway such as inhibiting myd88 could ameliorate liver injuries and fibrosis.Taken together,these findings indicate potential therapies for the treatment of MAFLD progression.

关键词： S100A4 myd88 metabolism

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大黄鱼DIGIRR通过抑制myd88-NF-κB的激活参与免疫调控

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水产学报 2024年第5期48卷 3-14页

作者：罗云江柳盈姚翠鸾集美大学水产学院海水养殖生物育种全国重点实验室

为研究大黄鱼双免疫球蛋白白细胞介素1受体相关分子(double immunoglobulin interleukin-1 receptor-related molecule, DIGIRR)在免疫反应中的作用，本实验克隆了大黄鱼digirr (Lcdigirr)的编码区序列；采用荧光定量PCR (qPCR)对大黄鱼各组织及免疫刺激后的脾脏、头肾等组织及大黄鱼肾细胞系(LCK)中的Lcdigirr表达情况进行了检测；构建了重组表达质粒pTurboGFP-DIGIRR及pcDNA3.1-DIGIRR，分别以绿色荧光蛋白(GFP)为报告基因及双荧光素酶报告系统，研究了Lc DIGIRR的亚细胞定位及过表达后对NF-κB启动子活性的调控。结果显示，Lcdigirr的开放读码框(ORF)包含1 575 bp核苷酸，编码524个氨基酸，理论分子量为59.4 ku、等电点(pI)为5.76,N端包含2个免疫球蛋白(Ig)结构域、1个跨膜区及1个Toll/白细胞介素-1受体(TIR)结构域，属于保守的硬骨鱼类DIGIRR家族；qPCR结果显示，Lcdigirr在大黄鱼多组织均有表达，其中在肠道中表达量最高；采用变形假单胞菌及脂多糖(LPS)、鞭毛蛋白、多聚肌-胞苷酸[poly (I:C)]等分别进行体内与体外刺激，均可诱导其表达量显著增加；亚细胞定位结果显示，Lc DIGIRR主要存在于细胞的膜质区；过表达Lc DIGIRR能够显著抑制nf-κb及myd88介导的nf-κb的转录激活。综上表明，Lcdigirr可能通过抑制nf-κb的转录激活，在大黄鱼的免疫反应中发挥负调控作用。对于深入理解大黄鱼的免疫反应机制具有重要意义。

关键词：大黄鱼 DIGIRR 表达特征过表达 myd88 NF-кB 负调控

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多发性硬化中TLRs/myd88/NF-κB信号通路的作用及机制

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中国组织工程研究 2024年第28期28卷 4578-4585页

作者：陈莹夏天晴滑键林殷金珠宋丽娟王青尉杰忠黄建军马存根山西中医药大学神经生物学研究中心/国家中医药管理局多发性硬化益气活血重点研究室山西省晋中市030619 国药同煤集团总医院神经外科山西省大同市037003 山西大同大学脑科学研究所山西省大同市037009

背景:多发性硬化是以T细胞介导的中枢神经系统慢性炎性脱髓鞘疾病,Toll样受体(Toll-like receptors,TLRs)/髓样分化因子88(myeloid differentiation factor 88,myd88)/核转录因子κB(nuclear factor kappa-B,NF-κB)信号通路在疾病发生发展过程中有重要作用,探究出信号通路的具体作用机制对进一步治疗该疾病,改善患者的预后至关重要。目的:综述TLRs/myd88/NF-κB信号通路及其在多发性硬化/实验性自身免疫性脑脊髓炎模型中的作用,并就抑制该信号通路为多发性硬化的治疗提供新的思路和策略。方法:检索中国知网、万方及PubMed数据库在2002年1月至2022年12月与文章主题相关的文献,最终纳入61篇文献进行分析。结果与结论:①TLRs/myd88/NF-κB信号通路是介导炎性免疫反应的重要信号通路;②TLRs/myd88/NF-κB信号通路通过调节树突状细胞的抗原提呈、破坏血脑屏障的完整性、促进T细胞、B细胞和小胶质细胞的激活等途径,在多发性硬化的发展中发挥了重要的作用;③通过靶向作用于TLRs、myd88和NF-κB分子,抑制TLRs、myd88和NF-κB的激活或信号传导,减少促炎因子的分泌可以达到治疗多发性硬化的目的;④动物实验研究表明,中药的活性成分如黄酮类和苷类、中药复方如补阳还五汤也可通过影响TLRs/myd88/NF-κB信号通路治疗实验性自身免疫性脑脊髓炎,这为寻找靶向TLRs/myd88/NF-κB信号通路治疗多发性硬化的药物指明方向。

关键词：多发性硬化 TLRs myd88 NF-κB 小胶质细胞炎症反应机制治疗

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通平脂肝方对非酒精性脂肪肝小鼠肝组织炎症及TLR4/myd88/NF-κB通路的影响

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河北中医药学报 2024年第2期39卷 1-6页

作者：王硕徐文轩申明宇李超喇孝瑾李继安齐亚娟王秀萍吴哲华北理工大学中医学院唐山063210 华北理工大学基础医学院唐山063210 河北省农林科学院滨海农业研究所唐山063210

目的:基于TOLL样受体4(TLR4)介导的髓样分化因子88(myd88)/核因子-κB(NF-κB)通路探讨通平脂肝方对高脂饲料诱导的非酒精性脂肪肝(non-alcoholicfattyliverdisease, NAFLD)模型小鼠的肝脏保护作用及抑制炎症的相关机制。方法:选用C57BL... 详细信息

目的:基于TOLL样受体4(TLR4)介导的髓样分化因子88(myd88)/核因子-κB(NF-κB)通路探讨通平脂肝方对高脂饲料诱导的非酒精性脂肪肝(non-alcoholicfattyliverdisease, NAFLD)模型小鼠的肝脏保护作用及抑制炎症的相关机制。方法:选用C57BL/6J雄性小鼠60只,随机分为正常、模型、盐酸吡格列酮和通平脂肝方低、中、高剂量组,各10只。给药8 w后取材。结果:与正常组相比,模型组体质量、血脂、肝功能、IL-6、TNF-α及TLR4、myd88、Ikkβ、NF-κB蛋白和TLR4、myd88、Ikkβ的mRNA表达水平均上升(Pmyd88/NF-κB信号通路,抑制脂质合成及炎症因子的表达有关。

关键词：非酒精性脂肪肝炎症通平脂肝方 TLR4 myd88 Ikkβ NF-κB

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Apigenin ameliorates diabetic neuropathy in rats by modulating the TLR4/myd88 signaling pathway

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Asian Pacific Journal of Tropical Biomedicine 2023年第11期13卷 469-478,I0003,I0004,I0005,I0006,I0008页

作者： Yan-Bo Yu Mi-Zhen Qiu Da-Ying Zhang Department of Pain The First Affiliated Hospital of Nanchang UniversityNanchang 330006China

Objective:To determine the neuroprotective effects of apigenin against streptozotocin(STZ)-induced diabetic neuropathy(DN).Methods:To induce DN,Wistar rats(150-200 g)were administered with STZ(55 mg/kg,i.p.).Then they were randomly assigned to various groups,viz.,normal,diabetic control,insulin(10 IU/kg,s.c.),apigenin(5,10,and 20 mg/kg,p.o.),and insulin(10 IU/kg)plus apigenin(20 mg/kg,p.o.).Various behavioral,biochemical,and molecular markers[tumor necrosis factor-alpha(TNF-α),interleukin(IL)-1β,IL-6,Toll-like receptor 4(TLR4),myeloid differentiation primary response 88(myd88),and nuclear factor erythroid 2-related factor 2(Nrf2)]were assessed.Results:Apigenin(10 and 20 mg/kg,p.o.)substantially reduced plasma glucose levels,lipid profile,aspartate transaminase,alanine transaminase,glycated hemoglobin,and neural advanced glycation end products in STZ-induced DN rats(Pmyd88(Pmyd88 signaling pathway.

关键词： Apigenin Diabetic neuropathy myd88 Nrf2 Proinflammatory cytokines TLR4

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HSA-MIR-203/myd88 axis mediates the protective effect of hispidulin on LPS-induced apoptosis in a human renal tubular epithelial line,HK-2

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BIOCELL 2022年第1期46卷 149-158页

作者： SICONG WANG RUIJIN LIU QIUYUAN HAN KAIJIANG YU Department of Critical Care Medicine The Second Affiliated Hospital of Harbin Medical UniversityHarbin150001China Department of Critical Care Medicine The Cancer Hospital of Harbin Medical UniversityHarbin150081China Department of Critical Care Medicine The First Affiliated Hospital of Harbin Medical UniversityHarbin150001China

Acute kidney injury(AKI),commonly occurring as complications of sepsis,cardiac surgery,and liver or kidney transplantation,is a critical care syndrome.It is well known that lipopolysaccharide(LPS)shock is a common triggering factor for AKI.This study is aimed to examine the effect of flavonoid compound hispidulin on LPS-induced AKI.For this,renal tubular epithelial cell HK-2 was treated with LPS to establish an in vitro model of AKI.The effect of hispidulin on HK-2 cell viability was examined using CCK-8 assay.Cell apoptosis was determined by TUNEL and flow cytometry.Apoptosis marker proteins were determined by using western blot.The levels of pro-inflammatory cytokines were determined by ELISA assay and qRT-PCR.The translocation of NF-κB was determined by western blot.The effect of myd88 on the cytoprotective activities of hispidulin was examined by overexpressing myd88 in HK-2 cells.Our results showed that hispidulin was not able to produce a cytotoxic effect on HK-2 cells at tested concentrations.However,hispidulin could protect HK-2 cells from LPS-induced cell injury.Our results also showed that hispidulin was able to attenuate LPS-induced HK-2 cell apoptosis.In addition,LPS led to an inflammatory response in HK-2 cells,evidenced by NF-κB p65 activation as well as increased expression and release of inflammatory cytokine IL-6 and TNF-α,which could be reversed by pretreatment with hispidulin.Overexpression myd88 was found to significantly dampen the cytoprotective activities of hispidulin against LPS insult.More importantly,myd88 was identified as a direct target of hsa-miR-203,and hispidulin was found to regulate the expression of myd88 via upregulating hsa-miR-203.Our results showed that hispidulin attenuates LPS-induced HK-2 damage via regulating hsa-miR-203/myd88 axis.

关键词： Hispidulin LPS HK-2 hsa-miR-203 myd88

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鰤鱼诺卡氏菌疫苗对石斑鱼免疫效果研究

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中国农业科技导报 2024年第2期26卷 145-152页

作者：高浩峰邵蓬武尊吴雅婷汪笑宇天津农学院水产学院天津市水产生态及养殖重点实验室天津300392 天津市水产研究所天津300392

为探究鰤鱼诺卡氏菌灭活疫苗对石斑鱼的免疫效果,通过免疫基因表达量分析疫苗对石斑鱼的免疫保护。利用鰤鱼诺卡氏菌制备福尔马林灭活全菌疫苗,通过腹腔注射法对珍珠龙胆石斑鱼进行免疫,利用荧光定量法检测免疫后该鱼的肾脏、肝脏和脾3... 详细信息

为探究鰤鱼诺卡氏菌灭活疫苗对石斑鱼的免疫效果,通过免疫基因表达量分析疫苗对石斑鱼的免疫保护。利用鰤鱼诺卡氏菌制备福尔马林灭活全菌疫苗,通过腹腔注射法对珍珠龙胆石斑鱼进行免疫,利用荧光定量法检测免疫后该鱼的肾脏、肝脏和脾3个器官中TLR2、myd88、TNF-α、IL-1β免疫基因表达量的变化。结果显示,注射灭活疫苗后,TNF-α、IL-1β基因表达量在肾脏组织中较高,myd88基因表达量在脾组织中较高,TLR2基因表达量在肝脏组织中较高;除脾组织中的TNF-α基因相对表达量出现下降趋势外,其余基因的表达量在所有器官中都呈现出上调的趋势。研究结果为探索珍珠龙胆石斑鱼与诺卡氏菌的相互作用提供理论基础,为渔业疫苗开发和应用奠定基础。

关键词：鰤鱼诺卡氏菌石斑鱼灭活疫苗 TLR2 myd88 TNF-α IL-1β

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Molecular Cloning and Functional Characterization of Porcine myd88 Essential for TLR Signaling

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Cellular & Molecular Immunology 2007年第5期4卷 369-376页

作者： Masanori Tohno Tomoyuki Shimazu Hisashi Aso Yasushi Kawai Tadao Saito Haruki Kitazawa Food Immunology Group Laboratory of Animal Products ChemistryGraduate School of Agricultural ScienceTohoku UniversityAobakuSendai 981-8555Japan Research Fellow of the Japan Society for the Promotion of Science Food Immunology Group Laboratory of Animal Products ChemistryGraduate School of Agricultural ScienceTohoku UniversityAobakuSendai 981-8555Japan Laboratory of Functional Morphology Graduate School of Agricultural ScienceTohoku UniversityAobakuSendai 981-8555Japan

We isolated cDNA encoding porcine myd88 （pomyd88） from Peyer＇s patches （Pps） of GALT. The complete open reading frame （ORF） of pomyd88 contains 879 bp encoding a deduced 293 aa residues. The amino acid sequence of pomyd88 was characterized by N-terminal death, intermediate and C-terminal Toll/IL-1 receptor （TIR） domains. The putative pomyd88 protein shares a higher level of homology with its human （87.2% amino acid identity） than with its mouse （77.4% amino acid identity） counterpart. Overexpression of pomyd88 participated in the further enhanced activation of NF-w.B in human embryonic kidney （HEK） 293 cells expressing porcine TLR2 and porcine TLR4/MD-2, but not porcine RP105/MD-1 after stimulation with the corresponding ligands. The expression levels of myd88 were highest in the spleen and mesenteric lymph nodes （MLNs）, and lower in digestive tissues of newborn swine. In adult swine, the expression levels in the digestive tissues were lower than those in MLNs and the spleen. These results suggest that an myd88-dependent signaling pathway is present in newborn as well as in adult swine and that it is involved in the innate immune system of these animals.

关键词： myd88 TLR2 TLR4/MD-2 RP105/MD-1 cDNA cloning swine

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SPOP negatively regulates Toll-like receptor-induced inflammation by disrupting myd88 self-association

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Cellular & Molecular Immunology 2021年第7期18卷 1708-1717页

作者： Yun-Hong Hu Yang Wang Fei Wang Yan-Ming Dong Wan-Ling Jiang Ya-Ping Wang Xing Zhong Li-Xin Ma State Key Laboratory of Biocatalysis and Enzyme Engineering School of Life SciencesHubei UniversityWuhan430062China School of Biological and Chemical Engineering College of ZhixingHubei UniversityWuhan430011China

Toll-like receptor(TLR)signaling pathways need to be tightly controlled to avoid excessive inflammation and unwanted damage to the host.Myeloid differentiation primary response gene 88(myd88)is a critical adaptor of TLR signaling.Here,we identified the speckle-type POZ protein(SPOP)as a myd88-associated protein.SPOP was recruited to myd88 following TLR4 activation.TLR4 activation also caused the translocation of SPOP from the nucleus to the cytoplasm.SPOP depletion promoted the aggregation of myd88 and recruitment of the downstream signaling kinases IRAK4,IRAK1 and IRAK2.Consistently,overexpression of SPOP inhibited the TLR4-mediated activation of NF-κB and production of inflammatory cytokines,whereas SPOP depletion had the opposite effects.Furthermore,knockdown of SPOP increased myd88 aggregation and inflammatory cytokine production upon TLR2,TLR7 and TLR9 activation.Our findings reveal a mechanism by which myd88 is regulated and highlight a role for SPOP in limiting inflammatory responses.

关键词： SPOP myd88 TLR inflammation

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Cardamine komarovii flower extract reduces lipopolysaccharide-induced acute lung injury by inhibiting myd88/TRIF signaling pathways

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Chinese Journal of Natural Medicines 2019年第6期17卷 461-468页

作者： CHEN Qi ZHANG Ke-Xin LI Tai-Yuan PIAO Xuan-Mei LIAN Mei-Lan AN Ren-Bo JIANG Jun Key Laboratory of Natural Resource of Changbai Mountain and Functional Molecules(Ministry of Education) Yanbian UniversityYanji 133002China Agricultural College Yanbian UniversityYanji 133002China Department of Urology College of MedicineChungbuk National UniversityCheongju 28644Republic of Korea

In the present study, we investigated anti-inflammatory effect of Cardamine komarovii flower(CKF) on lipopolysaccharide(LPS)-induced acute lung injury(ALI). We determined the effect of CKF methanolic extracts on LPS-induced pro-inflammatory mediators NO and prostaglandin E2(PGE2), production of pro-inflammatory cytokines(IL-1β, TNF-α, and IL-6), and related protein expression levels of myd88/TRIF signaling pathways in peritoneal macrophages(PMs). Nuclear translocation of NF-κB-p65 was analyzed by immunofluorescence. For the in vivo experiments, an ALI model was established to detect the number of inflammatory cells and inflammatory factors(IL-1β, TNF-α, and IL-6) in bronchoalveolar lavage fluid(BALF) of mice. The pathological damage in lung tissues was evaluated through H&E staining. Our results showed that CKF can decrease the production of inflammatory mediators, such as NO and PGE2, by inhibiting their synthesis-related enzymes i NOS and COX-2 in LPS-induced PMs. In addition, CKF can downregulate the mRNA levels of IL-1β, TNF-α, and IL-6 to inhibit the production of inflammatory factors. Mechanism studies indicated that CKF possesses a fine anti-inflammatory effect by regulating My D88/TRIF dependent signaling pathways. Immunocytochemistry staining showed that the CKF extract attenuates the LPS-induced translocation of NF-kB p65 subunit in the nucleus from the cytoplasm. In vivo experiments revealed that the number of inflammatory cells and IL-1β in BALF of mice decrease after CKF treatment. Histopathological observation of lung tissues showed that CKF can remarkably improve alveolar clearance and infiltration of interstitial and alveolar cells after LPS stimulation. In conclusion, our results suggest that CKF inhibits LPS-induced inflammatory response by inhibiting the myd88/TRIF signaling pathways, thereby protecting mice from LPS-induced ALI.

关键词： Cardamine komarovii flower Inflammation myd88 TRIF Acute lung injury

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