MAP1B‐LC1 prevents autophagosome formation by linking syntaxin 17 to microtubules

In fed cells, syntaxin 17 (Stx17) is associated with microtubules at the endoplasmic reticulum–mitochondria interface and promotes mitochondrial fission by determining the localization and function of the mitochondrial fission factor Drp1. Upon starvation, Stx17 dissociates from microtubules and Drp1, and binds to Atg14L, a subunit of the phosphatidylinositol 3‐kinase complex, to facilitate phosphatidylinositol 3‐phosphate production and thereby autophagosome formation, but the mechanism underlying this phenomenon remains unknown. Here we identify MAP1B‐LC1 (microtubule‐associated protein 1B‐light chain 1) as a critical regulator of Stx17 function. Depletion of MAP1B‐LC1 causes Stx17‐dependent autophagosome accumulation even under nutrient‐rich conditions, whereas its overexpression blocks starvation‐induced autophagosome formation. MAP1B‐LC1 links microtubules and Stx17 in fed cells, and starvation causes the dephosphorylation of MAP1B‐LC1 at Thr217, allowing Stx17 to dissociate from MAP1B‐LC1 and bind to Atg14L. Our results reveal the mechanism by which Stx17 changes its binding partners in response to nutrient status.     

RKIP mediates autoimmune inflammation by positively regulating IL‐17R signaling

Th17 cells contribute to the development of autoimmune diseases by secreting interleukin‐17 (IL‐17), which activates its receptor (IL‐17R) that is expressed on epithelial cells, macrophages, microglia, and resident neuroectodermal cells. However, the mechanisms through which IL‐17R‐mediated signaling contributes to the development of autoimmune disease have not been completely elucidated. Here, we demonstrate that Raf‐1 kinase inhibitor protein (RKIP) deficiency in mice ameliorates the symptoms of experimental autoimmune encephalomyelitis (EAE). Adoptive T‐cell‐transfer experiments demonstrate that RKIP plays a predominant role in Th17‐mediated, but not in Th1‐mediated immune responses. RKIP deficiency has no effect on Th17‐cell differentiation ex vivo, nor does it affect Th17‐cell differentiation in EAE mice. However, RKIP significantly promotes IL‐17R‐induced proinflammatory cytokine and chemokine production. Mechanistically, RKIP directly interacts with IL‐17RA and Act1 to promote the formation of an IL‐17R‐Act1 complex, resulting in enhanced MAPK‐ and P65‐mediated NF‐κB activation and downstream cytokine production. Together, these findings indicate that RKIP functions as an essential modulator of the IL‐17R‐Act1 axis in IL‐17R signaling, which promotes IL‐17‐induced inflammation and autoimmune neuroinflammation.     

艾拉莫德片联合双醋瑞因治疗类风湿关节炎的临床疗效及对患者血清IL-17、IL-23水平的影响

目的:探讨艾拉莫德片联合双醋瑞因治疗类风湿关节炎的临床疗效及对患者血清白介素(IL)-17、IL-23水平的影响。方法:选择2015年9月至2017年9月我院接诊的96例类风湿关节炎患者,通过随机数表法将其分为观察组(n=48)和对照组(n=48),两组均给予甲氨蝶呤片及常规对症治疗,对照组在此基础上给予艾拉莫德片治疗,观察组在对照组的基础上联合双醋瑞因胶囊治疗,两组均以4周为1个疗程,连续治疗6个疗程。比较两组的临床疗效、治疗前后临床症状评分、实验室指标[红细胞沉降率(ESR)、C反应蛋白(CRP)、类风湿因子(RF)]、免疫学指标[免疫球蛋白(Ig)G、IgA、IgM]及血清IL-17、IL-23水平的变化及治疗期间不良反应的发生情况。结果:治疗后,观察组临床疗效总有效率为89.58%(43/48),明显高于对照组的70.83%(34/48)(P0.05);两组关节疼痛、关节压痛、关节肿胀、晨僵时间评分、ESR、CRP、RF、IgG、IgA、IgM较治疗前均显著降低(P0.05),观察组以上指标均明显低于对照组(P0.05);两组血清IL-17、IL-23水平均较治疗前显著降低(P0.05),观察组血清IL-17、IL-23水平均明显低于对照组[(11.23±1.30)pg/ml vs(16.49±1.79)pg/mL,(83.41±10.25)pg/mL vs(103.52±12.47)pg/mL](P0.05)。两组治疗期间药物不良反应总发生率比较无显著差异(P0.05)。结论;艾拉莫德片联合双醋瑞因治疗类风湿关节炎患者的效果显著,可明显改善患者的临床症状,促进关节功能恢复,其内在机制可能和降低血清IL-17、IL-23的表达相关。     

IL-17A在呼吸道慢性炎症性疾病中的研究进展

白介素-17A(IL-17A)是一种促炎因子,是IL-17细胞因子家族中的一员。该家族的细胞因子分别被命名为IL-17A至IL-17F,IL-17A是该家族中最具代表性的成员,它能够促进炎症细胞释放多种趋化因子、细胞因子和抗菌肽等,诱导中性粒细胞的聚集和增殖,是连接固有免疫和适应性免疫的桥梁。IL-17A的家族细胞因子在很多肺部过敏性、自身免疫性甚至肿瘤性疾病的发生发展和宿主防御中发挥着关键作用,在哮喘、慢性阻塞性肺病(COPD)、囊性纤维化(CF)、结节病、支气管扩张等呼吸道慢性炎症性疾病中均存在异常表达,虽然在多种疾病中未能阐明IL-17A影响疾病发展的具体作用机制,但已证明其水平与疾病的发展存在关联,这不仅为研究相关疾病的发病机制提供了新的切入点,也为其新型治疗手段的研究提供了新的思路。本文就IL-17A在呼吸道慢性炎症性疾病中的研究进展进行综述。     

Enteroviral Infection Inhibits Autophagic Flux via Disruption of the SNARE Complex to Enhance Viral Replication

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CD209a Synergizes with Dectin-2 and Mincle to Drive Severe Th17 Cell-Mediated Schistosome Egg-Induced Immunopathology

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S100A9 gene silencing inhibits the release of pro‐inflammatory cytokines by blocking the IL‐17 signalling pathway in mice with acute pancreatitis

The study aimed to investigate whether S100A9 gene silencing mediating the IL‐17 pathway affected the release of pro‐inflammatory cytokines in acute pancreatitis (AP). Kunming mice were assigned to the normal, AP, AP + negative control (NC), AP + shRNA, AP + IgG and AP + anti IL‐17 groups. ELISA was applied to measure expressions of AMY, LDH, CRP, TNF‐α, IL‐6 and IL‐8. The cells were distributed into the control, blank, NC, shRNA1 and shRNA2 groups. MTT assay, flow cytometry, RT‐qPCR and Western blotting were used to evaluate cell proliferation, cell cycle and apoptosis, and expressions of S100A9, TLR4, RAGE, IL‐17, HMGB1 and S100A12 in tissues and cells. Compared with the normal group, the AP group displayed increased expressions of AMY, LDH, CRP, TNFα, IL‐6, IL‐8, S100A9, TLR4, RAGE, IL‐17, HMGB1 and S100A12. The AP + shRNA and AP + anti IL‐17 groups exhibited an opposite trend. The in vivo results: Compare with the control group, the blank, NC, shRNA1 and shRNA2 groups demonstrated increased expressions of S100A9, TLR4, RAGE, IL‐17, HMGB1 and S100A12, as well as cell apoptosis and cells at the G1 phase, with reduced proliferation. Compared with the blank and NC groups, the shRNA1 and shRNA2 groups had declined expressions of S100A9, TLR4, RAGE, IL‐17, HMGB1 and S100A12, as well as cell apoptosis and cells at the G1 phase, with elevated proliferation. The results indicated that S100A9 gene silencing suppressed the release of pro‐inflammatory cytokines through blocking of the IL‐17 pathway in AP.     

Spline Optimum Regression Method and Its Application

IIntroductionUsuallyinersareseveralIntervalsIngrowingcurvesInorganisms,suchas,thecurvesofre－productlvltyandactivity．ThereareessentialdifferencesIntheInternaldevelopinglawsonthedlf－ferentIntervals,therefore,ItIsnotacceptabletotlsesingleelementaryfunctiontofitthecurves．TofitcurvesonalltheIntervalswithsmoothnessorcontinuancebetweenIntervals,asplinefunct;onIsrequired（Robinson1983;Yangetal,1992ah）．Splineregresslonandmethodsforflitinganoptimumsplinefunctionhavelongbeenstudied（…