Soluble mannose receptor induces proinflammatory macrophage activation and metaflammation

Proinflammatory activation of macrophages in metabolic tissues is critically important in the induction of obesity-induced metaflammation. Here, we demonstrate that the soluble mannose receptor (sMR) plays a direct functional role in both macrophage activation and metaflammation. We show that sMR binds CD45 on macrophages and inhibits its phosphatase activity, leading to an Src/Akt/NF-κB–mediated cellular reprogramming toward an inflammatory phenotype both in vitro and in vivo. Remarkably, increased serum sMR levels were observed in obese mice and humans and directly correlated with body weight. Importantly, enhanced sMR levels increase serum proinflammatory cytokines, activate tissue macrophages, and promote insulin resistance. Altogether, our results reveal sMR as regulator of proinflammatory macrophage activation, which could constitute a therapeutic target for metaflammation and other hyperinflammatory diseases.

Metaflammation defines a chronic inflammatory state in response to prolonged excessive nutrient intake and is characterized by low-grade inflammation of metabolic tissues (1). Macrophage reprogramming toward an inflammatory phenotype plays a critical role in obesity-induced metaflammation (2, 3). In lean individuals, macrophages in metabolic tissues maintain tissue homeostasis and insulin sensitivity, potentially through secreting anti-inflammatory cytokines, for example, TGF-β and IL-10 (1). In metaflammation, however, macrophages in adipose tissue and liver are activated through proinflammatory factors in their microenvironment, such as high levels of saturated free fatty acids (FA) and IFN-γ. Consequently, these macrophages produce high amounts of tumor necrosis factor (TNF), which directly inhibits canonical insulin signaling (4), leading to ectopic fat deposition in the liver and in skeletal muscles (5). Additionally, activation of Kupffer cells (KCs), the liver-resident macrophages, promotes recruitment and activation of inflammatory monocytes, which contribute to hepatic insulin resistance and steatosis (6–8).The MR (also termed CD206) is a type I transmembrane protein belonging to the C-type lectin family, which is mainly expressed by subpopulations of macrophages, dendritic cells, and endothelial cells (9, 10). The MR consists of a cysteine-rich region, a fibronectin type II domain, eight C-type lectin-like domains (CTLDs), a transmembrane region, and a short cytosolic tail. Due to its high affinity for glycosylated antigens, the MR plays an important role in antigen uptake and presentation (11, 12). In addition to its functions as a transmembrane protein, the extracellular part of the MR can be shed by metalloproteases and released into the extracellular space (13, 14). Hence, soluble MR (sMR) can be detected in murine and human serum, and its level was found to be increased in patients with a variety of inflammatory diseases (15–20), correlating with severity of disease and even mortality. However, a physiological role of the sMR has not been studied yet, and it remains unclear whether the sMR can actively trigger inflammation.Here, we report that sMR enhances macrophage proinflammatory activation, both in vitro and in vivo, and promotes metaflammation. We demonstrate that the sMR directly interacts with CD45 on the surface of macrophages and inhibits its phosphatase activity, leading to Src/Akt/NF-κB–mediated cellular reprogramming toward an inflammatory phenotype. Additionally, we found enhanced sMR serum levels in obese mice and humans and show that sMR-induced activation of macrophages triggers metaflammation in vivo.     

IKBKE与肿瘤研究进展

IKBKE又称为IKK￡或IKKi,是IκB激酶家族的新成员.通过调节干扰素和核转录因子κB途径,IKBKE在调节固有免疫中发挥重要作用.此外,IKBKE和多种肿瘤的发生发展相关,它调控细胞扩增及恶性转化,在肿瘤发生发展过程中扮演着致癌基因的角色.近年来本文就IKBKE分子结构、致瘤分子机制、在相关肿瘤的研究及抑制剂进展作一综述.     

NLRP3炎症小体及其激活产物在慢性阻塞性肺疾病中的作用研究进展

慢性阻塞性肺疾病(COPD)是一种常见的以持续气流受限为特征的疾病,与气道和肺对有毒颗粒或气体的慢性炎症反应增强有关.COPD发病率、致死率高,造成了严重的经济和社会负担.然而迄今为止,没有一种治疗COPD的药物可以有效地阻止疾病的进展.目前认为,气道和肺部的慢性炎症是导致COPD发生发展的主要机制.然而促使炎症产生并大量扩散的机制尚不清楚.炎症小体最近被发现在呼吸系统疾病的炎症发生发展中发挥重要作用.种种证据表明香烟烟雾导致NLRP3炎症小体的活化,促使IL-1β和IL-18的成熟和释放增多,可能在COPD的慢性炎症中发挥重要作用,为临床上治疗COPD提供了新的思路.     

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代谢异常巳成为我国高血压患病率升高的主要原因,代谢性高血压巳成为高血压的主要临床类型,其发病机制除涉及经典血压调控途径外,尚与免疫炎症关系密切。另外,血压调控器官的代谢性损害也是血压升高的重要原因。目前的高血压药物治疗对高血压合并代谢异常的控制有一定局限性,探索新的治疗策略是面临的新挑战。     

流感病毒感染中炎症小体的激活和调控机制

炎症反应是宿主抗流感病毒感染的一个重要过程,它可以诱导产生抗病毒的炎症微环境以减少病毒的复制和扩散,同时参与对流感病毒的适应性免疫反应,在机体抗流感病毒感染过程中至关重要.然而,过度的炎症反应同时也是流感病毒重症感染、甚至死亡的主要因素.研究表明,炎症小体作为炎症反应的重要启动和调节分子,介导IL-1β和IL-18的成...     

Role of NLRP3 inflammasome in liver disease

Inflammasomes have become an important natural sensor of host immunity, and can protect various organs against pathogenic infections, metabolic syndromes, cellular stress and cancer metastasis. Inflammasomes are intracellular multi‐protein complexes found in both parenchymal and non‐parenchymal cells, stimulating the initiation of caspase‐1 and interleukin (IL)‐1β and IL‐18 in response to cell danger signals. Inflammasomes induce cell death mechanisms. The potential role of NOD‐like receptor protein 3 (NLRP3) inflammasome in alcoholic and non‐alcoholic steatohepatitis, hepatitis, nanoparticle‐induced liver injury and other liver diseases has recently attracted widespread attention from clinicians and researchers. In this review we summarize the role played by the NLRP3 inflammasome in molecular and pathophysiological mechanisms in the pathogenesis and progression of liver disease. This article aims to establish that targeting the NLRP3 inflammasome and other inflammasome components may make a significant therapeutic approach to the treatment of liver disease.     

NLRP3炎症小体在动脉粥样硬化中的作用机制和靶向炎症治疗的研究进展

动脉粥样硬化(As)是由一系列复杂因素引起的病理过程,包括内皮功能障碍、动脉血管壁中脂质沉积、巨噬细胞浸润、平滑肌细胞功能失调、泡沫细胞形成等,炎症反应在这一过程中发挥了重要的作用。NOD样受体热蛋白结构域相关蛋白3(NLRP3)炎症小体是炎症细胞的传导器,其激活后介导炎症反应,激活下游的白细胞介素18、白细胞介素1β,从而参与As的发生和发展。因此,针对NLRP3炎症小体和下游炎症因子的特异性抑制剂是目前临床药物研究的潜在靶点,有望成为治疗As的一种新的治疗措施。文章对NLRP3炎症小体的结构和激活机制及与As的关系进行了讨论,同时对靶向NLRP3炎症小体和下游炎症因子的药物进行了介绍。     

NLRP3炎症小体在海水吸入性急性肺损伤中的表达和作用

目的探讨海水吸入型急性肺损伤大鼠肺组织中NOD样受体热蛋白结构域相关蛋白3(NLRP3)炎症小体表达的变化及介导的炎性因子在急性肺损伤(ALI)发生发展中的作用。 方法将50只健康雄性SD大鼠随机分为5组,对照组,海水吸入1 h组,海水吸入3 h组,海水吸入6 h组,海水吸入9 h组,每组10只。采用经气管缓慢滴注(3 ml/kg)海水的方法制作大鼠损伤模型。制作大鼠肺脏石蜡切片并HE染色观察病理形态学变化。检测大鼠肺组织湿干比。ELISA检测测定各组肺组织中IL-1β和IL-18水平,RT-PCR检测肺组织中IL-1β、IL-18和NLRP3mRNA的表达。Western-blot检测肺组织中NLRP3蛋白表达。 结果气管滴注海水后成功复制海水吸入性急性肺损伤模型。肺组织湿干比较对照组显著升高。病理形态学观察可见肺组织大量炎细胞浸润、水肿、间质增厚。各组大鼠血清中IL-1β和IL-18的水平随着时间增加逐渐升高,且在3～6 h达到顶峰,随后炎症因子的表达逐渐降低。与空白对照组比较,差异均有统计学意义(均P<0.05)。各组大鼠肺组织中IL-1β和IL-18的mRNA的表达水平与大鼠肺组织中IL-1β和IL-18的表达基本一致。与空白对照组比较,差异均有统计学意义(均P<0.05)。肺组织匀浆中NLRP3转录和翻译结果显示海水吸入刺激后,肺组织中NLRP3的mRNA和NLRP3蛋白含量变化含量随着时间明显逐渐增加,差异均有统计学意义(均P<0.05)。 结论海水刺激下,NLRP3炎症小体介导的炎症反应参与了急性肺损伤发病过程并加重了肺损伤的程度,可能是海水急性肺损伤的发病机制之一,但其作用有待进一步证实。     

Nonpathogenic Lactobacillus rhamnosus activates the inflammasome and antiviral responses in human macrophages

In this study, we have utilized global gene expression profiling to compare the responses of human primary macrophages to two closely related, well-characterized Lactobacillus rhamnosus strains GG and LC705, since our understanding of the responses elicited by nonpathogenic bacteria in human innate immune system is limited. Macrophages are phagocytic cells of the innate immune system that perform sentinel functions to initiate appropriate responses to surrounding stimuli. Macrophages that reside on gut mucosa encounter ingested and intestinal bacteria. Bacteria of Lactobacillus genus are nonpathogenic and used in food and as supplements with health-promoting probiotic potential. Our results demonstrate that live GG and LC705 induced quantitatively different gene expression profiles in macrophages. A gene ontology analysis revealed functional similarities and differences in responses to GG and LC705 that were reflected in host defense responses. Both GG and LC705 induced interleukin-1β production in macrophages that required caspase-1 activity. LC705, but not GG, induced type I interferon -dependent gene activation that correlated with its ability to prevent influenza A virus replication and production of viral proteins in macrophages. Our results indicate that nonpathogenic bacteria are able to activate the inflammasome. In addition, our results suggest that L. rhamnosus may prime the antiviral potential of human macrophages.     

Nonpathogenic Lactobacillus rhamnosus activates the inflammasome and antiviral responses in human macrophages

In this study, we have utilized global gene expression profiling to compare the responses of human primary macrophages to two closely related, well-characterized Lactobacillus rhamnosus strains GG and LC705, since our understanding of the responses elicited by nonpathogenic bacteria in human innate immune system is limited. Macrophages are phagocytic cells of the innate immune system that perform sentinel functions to initiate appropriate responses to surrounding stimuli. Macrophages that reside on gut mucosa encounter ingested and intestinal bacteria. Bacteria of Lactobacillus genus are nonpathogenic and used in food and as supplements with health-promoting probiotic potential. Our results demonstrate that live GG and LC705 induced quantitatively different gene expression profiles in macrophages. A gene ontology analysis revealed functional similarities and differences in responses to GG and LC705 that were reflected in host defense responses. Both GG and LC705 induced interleukin-1β production in macrophages that required caspase-1 activity. LC705, but not GG, induced type I interferon -dependent gene activation that correlated with its ability to prevent influenza A virus replication and production of viral proteins in macrophages. Our results indicate that nonpathogenic bacteria are able to activate the inflammasome. In addition, our results suggest that L. rhamnosus may prime the antiviral potential of human macrophages.     

肺炎支原体感染RAW264.7细胞NLRP3炎性体及下游分子的表达

目的观察肺炎支原体(Mycoplasma pneunoniae,Mp)感染RAW264.7细胞早期NLRP3炎性体及前炎性细胞因子的表达。方法将RAW264.7细胞随机分为5组,正常组用常规方法培养,不感染Mp;4个实验组RAW264.7细胞均用Mp感染4h,感染复数(细胞︰Mp)分别为1︰20、1︰40、1︰80、1︰100,采用FQ-PCR法检测细胞NLRP3、ASC、caspase-1mRNA表达和IL-1β、IL-18水平。结果 Mp感染复数1︰20、1︰40、1︰80、1︰100组NLRP3、ASC、caspase-1mRNA表达量分别为2.10±0.62、2.14±0.66、2.66±0.69、3.29±0.64和3.91±0.83、4.21±0.95、4.25±0.86、4.30±0.99和1.65±0.48、1.65±0.36、1.94±0.51、2.00±0.57,与正常对照组0.98±0.08、1.00±0.08、0.99±0.09比较,差异均有统计学意义(P<0.01);感染复数1︰100组IL-1β为200.00±9.25pg/ml,与对照组159.92±5.89pg/ml比较差异有统计学意义(P<0.01)。结论 Mp感染可诱导RAW264.7细胞NLRP3炎性体活化。NLRP3炎性体可能参与了Mp的早期感染。     

NLRP3炎性体加重小鼠脑缺血再灌注损伤的机制探讨

目的：探讨Nod样受体蛋白3（NLRP3）炎性体（NLRP3蛋白、IL-1β、IL-8）在小鼠脑缺血再灌注损伤中的作用和机制。方法将C57BL／6小鼠随机分为对照组和格列本脲（ NLRP3抑制剂）组各20只,每组中一半小鼠通过大脑中动脉栓塞法构建缺血再灌注（ IR）模型,其余接受假手术处理。格列本脲组术前30 min腹腔注射500 mg／kg格列本脲。造模成功后对小鼠进行神经学评分,2,3,5,-氯化三苯基四氮唑染色,并计算缺血梗死面积,HE染色观察病理变化,TUNEL染色观察各组神经元凋亡情况,Western Blot检测小鼠脑组织NLRP3蛋白表达,ELISA检测小鼠脑组织中IL-1β、IL-18浓度。结果各组IR小鼠脑损伤程度均重于假手术小鼠,但是对照组IR小鼠脑损伤程度比格列本脲组严重。 HE染色和TUNEL染色显示,IR小鼠脑组织出现明显损伤,神经元凋亡数量明显增多,格列本脲可减轻IR造成的病理损伤程度。与对照组相比,格列本脲组的脑组织NLRP3蛋白表达及IL-1β、IL-18升高程度明显降低（ P均＜0．05）。结论 NLRP3炎性体可促进小鼠脑IR损伤,主要通过增加细胞因子释放和促进神经元凋亡实现的。     

NLRP3炎症小体在ICU获得性衰弱大鼠呼吸肌和下肢肌中的表达

目的探讨重症监护室获得性衰弱(ICU-AW)大鼠吸肌和下肢肌组织中NOD样受体热蛋白结构域相关蛋白3(NLRP3)炎症小体的表达及作用。 方法将40只健康雄性SD大鼠完全随机分为对照组(sham组)和实验组(脓毒血症组),采用盲肠结扎穿孔术在实验组大鼠中构建ICU-AW模型,对照组仅行开腹暴露盲肠手术;造模96 h后收集大鼠腓肠肌和膈肌标本,采用HE染色观察病理学变化并计算肌纤维横截面积,采用qRT-PCR和western blot的方法检测大鼠腓肠肌和膈肌中Atrogin-1、MuRF1、NLRP3、Caspase-1、IL-1β和IL-18的表达。 结果盲肠结扎穿孔术96 h后,大鼠腓肠肌和膈肌纤维排列较对照组疏松,肌纤维横截面积较对照组明显减少(P<0.05),Atrogin-1、MuRF1基因和蛋白表达量较对照组明显升高(P<0.05);ICU-AW大鼠腓肠肌和膈肌中NLRP3、Caspase-1、IL-1β和IL-18基因和蛋白表达量较对照组明显升高(P<0.05)。 结论盲肠结扎穿孔术制备的脓毒血症模型中,吸肌和下肢肌溶解参与ICU-AW的发生,NLRP3炎症小体相关信号通路参与上述过程。     

Therapeutic interventions target the NLRP3 inflammasome in ulcerative colitis: Comprehensive study

One of the significant health issues in the world is the prevalence of ulcerative colitis(UC). UC is a chronic disorder that mainly affects the colon, beginning with the rectum, and can progress from asymptomatic mild inflammation to extensive inflammation of the entire colon. Understanding the underlying molecular mechanisms of UC pathogenesis emphasizes the need for innovative therapeutic approaches based on identifying molecular targets. Interestingly, in response to cellular injury, the NLR ...     

细胞焦亡在心血管疾病中作用的研究进展

心血管疾病(CVD)已成为全球范围内的主要死亡原因之一.尽管目前对CVD的研究已取得一定进展,但仍有诸多问题有待进一步研究.近年新发现的细胞焦亡是一种伴随着炎症反应的细胞程序性死亡,研究显示其在CVD的发生发展中发挥重要作用.本文对细胞焦亡在动脉粥样硬化、心肌梗死、糖尿病性心肌病、心肌炎等CVD中的作用及机制进行了综述...     

药物性肝损伤慢性化的临床类型及特点

目的初步探讨药物性肝损伤(DILI)慢性化的临床类型及主要特点。方法筛选2011年1月-2013年12月在首都医科大学附属北京佑安医院住院诊断为DILI的病例,对其中的84例慢性DILI进行回顾性分析。所有入选病例均填写病例报告表,数据录入数据库,包括人口学特征、基础疾病、用药种类、主要症状和体征、实验室检查等。结果 84例患者中女性63例,占75.0%。根据病情发展和肝功能的恢复过程,可将DILI的慢性化过程分为6种临床类型,其中64例(76.2%)为反复发作型,4例(4.8%)为迁延不愈型,4例(4.8%)为反复波动型,6例(7.1%)为慢性胆汁淤积型,5例(6.0%)为快速进展至肝硬化型,1例(1.2%)为药物诱导的自身免疫性肝炎型。84例患者中56例(66.7%)患者存在基础疾病;由单一药物引起者有51例(60.7%),主要为中药(47.0%)、解热镇痛药(10.6%)和抗结核药(9.1%);肝损伤类型中肝细胞损伤型52例(61.9%)、胆汁淤积型8例(9.5%)、混合型5例(6.0%);肝脏生化学检查异常19例(22.6%)。结论 DILI的慢性化可分为6种临床类型,最常见的是反复发作型,其他还包括迁延不愈、反复波动、慢性胆汁淤积、快速进展至肝硬化和药物诱导的自身免疫性肝炎。