C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 pathway as a therapeutic target and regulatory mechanism for spinal cord injury

Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.

C–C motif chemokine ligand 16 inhibits the progression of liver cirrhosis via inactivating hepatic stellate cells

Background:Liver cirrhosis results from many forms of chronic damage,characterized by accumulation of extracellular matrix.The present study aimed to explore a potential non-invasive biomarker and its mechanism in the progression of liver cirrhosis.Methods:Gene Expression Omnibus(GEO)dataset(GSE15654,n=216)was analyzed to screen genes associated with progression of liver cirrhosis.A total of 181 plasma samples,including healthy control(HC,n=20),chronic hepatitis B(CHB,n=77)and HBV-related liver cirrhosis(LC,n=84),were enrolled for validation.In vitro and in vivo experiments were employed for the mechanistic investigation.Results:GEO dataset analysis showed that relatively low mRNA-expression of C–C motif chemokine ligand 16(CCL16)was associated with elevated Child-Pugh score(P=0.034)and worse prognosis(P=0.025).Plasma CCL16 level decreased in a stepwise pattern,with a median concentration of 10.29,6.57 and 4.47 ng/mL in the HC,CHB and LC groups,respectively(P<0.001).Low plasma CCL16 was significantly related to hepatic dysfunction both in the CHB and LC groups(P<0.05).Combination of CCL16 and ALT showed improved distinguishing capability for LC compared to either alone.In vitro,CCL16 expression was downregulated by lipopolysaccharide and hypoxia.Overexpression of CCL16 from human normal liver cell line(LO2)reduced the extracellular matrix associated proteins(Col1 and Col4)in human hepatic stellate cell line(LX-2).In vivo,the pathological feature of cirrhosis was alleviated by the hepatocytespecific expression of CCL16.Conclusions:CCL16 could be a feasible plasma marker to predict the occurrence and progression of liver cirrhosis.CCL16 might impact liver cirrhosis through inactivating hepatic stellate cells.

Macrophage migration inhibitory factor facilitates astrocytic production of the CCL2 chemokine following spinal cord injury

Spinal cord injury causes accumulation of a large number of leukocytes at the lesion site where they contribute to excessive inflammation.Overproduced chemokines are responsible for the migratory process of the leukocytes,but the regulatory mechanism underlying the production of chemokines from resident cells of the spinal cord has not been fully elucidated.We examined the protein levels of macrophage migration inhibitory factor and chemokine C-C motif chemokine ligand 2 in a spinal cord contusion model at different time points following spinal cord injury.The elevation of macrophage migration inhibitory factor at the lesion site coincided with the increase of chemokine C-C motif chemokine ligand 2 abundance in astrocytes.Stimulation of primary cultured astrocytes with different concentrations of macrophage migration inhibitory factor recombinant protein induced chemokine C-C motif chemokine ligand 2 production from the cells,and the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine attenuated the stimulatory effect.Further investigation into the underlying mechanism on macrophage migration inhibitory factor-mediated astrocytic production of chemokine C-C motif chemokine ligand 2 revealed that macrophage migration inhibitory factor activated intracellular JNK signaling through binding with CD74 receptor.Administration of the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine following spinal cord injury resulted in the reduction of chemokine C-C motif chemokine ligand 2-recruited microglia/macrophages at the lesion site and remarkably improved the hindlimb locomotor function of rats.Our results have provided insights into the functions of astrocyte-activated chemokines in the recruitment of leukocytes and may be beneficial to develop interventions targeting chemokine C-C motif chemokine ligand 2 for neuroinflammation after spinal cord injury.

结直肠癌根治术后血清CCL18、MMP-16水平与肿瘤复发、转移的关系

目的探讨腹腔镜下结直肠癌(CRC)根治术后患者血清C-C基序趋化因子配体18(CCL18)、基质金属蛋白酶-16(MMP-16)水平与肿瘤复发、转移的关系。方法选取2018年12月至2020年5月在保定市第二医院接受腹腔镜CRC根治术的125例CRC患者作为研究对象,根据随访情况,将其分为复发转移组和未复发转移组。采用酶联免疫吸附试验检测血清CCL18、MMP-16水平。绘制受试者工作特征(ROC)曲线分析CCL18、MMP-16对CRC患者术后发生肿瘤复发转移的预测价值。采用多因素Logistic回归分析CRC患者术后发生肿瘤复发转移的影响因素。结果随访结果显示,复发转移组37例和未复发转移组88例。复发组患者血清CCL18、MMP-16水平高于未复发组(P<0.05)。两组患者肿瘤最大径、TNM分期、淋巴结转移比较,差异均有统计学意义(P<0.05)。血清CCL18、MMP-16联合预测CRC患者术后发生肿瘤复发转移的曲线下面积(AUC)高于各指标单项检测的AUC(ZCCL18-联合=2.734,P=0.006;ZMMP-16-联合=3.327,P<0.001)。CCL18高表达(>1.58 ng/mL)患者3年复发转移率[70.73%(29/41)]高于CCL18低表达(≤1.58 ng/mL)患者[9.52%(8/84)],差异有统计学意义(χ^(2)=49.534,P<0.001)。MMP-16高表达(>143.46 ng/mL)患者3年复发转移率[71.11%(32/41)]高于MMP-16低表达(≤143.46 ng/mL)患者[6.25%(5/80)],差异有统计学意义(χ^(2)=58.143,P<0.001)。多因素Logistic分析结果显示,CCL18、MMP-16是CRC患者术后发生肿瘤复发转移的影响因素(P<0.05)。结论CRC根治术后患者血清CCL18、MMP-16水平较高,与肿瘤复发、转移密切相关。

ZCCHC10通过激活P53促进急性髓系白血病细胞中CCL18基因的转录

肿瘤抑制因子P53是一种转录因子,可激活一系列靶基因的转录,从而调控细胞周期停滞、DNA修复、免疫、炎症和细胞凋亡等多种生理或病理过程。前期研究表明,CCHC型锌指蛋白10(zinc finger CCHC-type containing 10,ZCCHC10)通过激活P53在肺癌和急性髓系白血病中发挥抑癌作用。为进一步探讨ZCCHC10在急性髓系白血病中的作用机制,本文通过RNA测序(RNA sequencing,RNA-seq)技术对过表达ZCCHC10或空载体的ML2细胞进行了转录组分析,一共鉴定到1284个差异基因[|log2(fold change)|逸1,q值约0.05],包括778个上调基因和506个下调基因。其中,趋化因子CCL18在过表达ZCCHC10的ML2细胞中上调18倍。生物信息学分析显示,CCL18基因启动子上含有两个P53反应元件。生物素标记DNA亲和实验和染色质免疫共沉淀实验证实,P53可结合到CCL18基因启动子上。荧光素酶活性分析表明,P53可以增强CCL18基因启动子的活性。这些研究表明ZCCHC10通过激活P53促进CCL18基因的表达。

“天龙竭”论治方案对晚期特发性肺间质纤维化患者肺功能及血清涎液化糖链抗原-6、趋化因子18的影响

目的 探讨“天龙竭”论治方案对特发性肺间质纤维化(IPF)晚期患者肺功能及血清涎液化糖链抗原-6(KL-6)、血清趋化因子18(CCL18)的影响。方法 采用随机双盲双模拟对照临床研究方法,将2020年1月至2021年1月云南中医药大学第三附属医院呼吸病学危重症医学专科36例晚期IPF患者,采用随机数字表法分为试验组和对照组,各18例。试验组采用“天龙竭”分期治疗方案,对照组采用吡非尼酮,疗程为3个月。观察治疗前后肺功能参数肺总量(TLC)、潮气量(TV)、单次呼吸法一氧化碳弥散(DLCO)及血清KL-6、CCL18水平,进行高分辨率CT(HRCT)治疗前后评分,并观察安全性指标。结果 治疗后,两组TLC、TV与治疗前比较及组间比较,差异无统计学意义(P>0.05),两组DLCO较治疗前升高,且试验组高于对照组,差异有统计学意义(P<0.05)。治疗后,两组HRCT评分与治疗前比较及组间比较,差异无统计学意义(P>0.05)。治疗后,两组治疗血清KL-6、CCL18水平较治疗前降低,差异有统计学意义(P<0.05)。两组治疗前后血清KL-6、CCL18水平比较,差异无统计学意义(P>0.05)。在治疗过程中,两组均未出现明显不良反应。结论 运用“天龙竭”方案可一定程度改善晚期IPF患者肺功能,并通过调控炎症反应稳定病情,临床应用安全有效。

Intestinal epithelial chemokine (C-C motif) ligand 7 overexpression protects against high fat diet-induced obesity and hepatic steatosis in mice

Background:We previously found that the intestinal epithelial chemokine(C-C motif)ligand 7(CCL7)plays an important role in the development of toxin-induced acute liver damage.The detailed effects of intestinal epithelial CCL7 on chronic diseases;however,are still unclear.Here,we aimed to investigate the impact of intestinal epithelial CCL7 overexpression on high-fat diet(HFD)-induced obesity and steatohepatitis in mice.Methods:Intestinal epithelial CCL7 overexpression(CCL7tgIEC)mice and their wild-type(WT)littermates were fed with normal chow or HFD for 16 weeks to induce obesity and non-alcoholic fatty liver disease.Body weight gain,as well as adipose tissue index were assessed.Liver injury was monitored by histological analysis and real time polymerase chain reaction.Gut microbial composition was analyzed by 16S rRNA gene sequencing.Results:We found that the CCL7tgIEC mice on a HFD had markedly decreased weight gain(8.9 vs.17.0 g,P<0.05)and a lower adipose tissue index that include mesenteric fat(1.0%vs.1.76%,P<0.05),gonadal fat(2.1%vs.6.1%,P<0.05),subcutaneous fat(1.0%vs.2.8%,P<0.05)compared to WT animals.HFD-induced glucose intolerance and insulin resistance were also significantly improved in CCL7tgIEC mice compared to WT.Furthermore,HFD-fed CCL7tgIEC mice displayed less hepatic lipid accumulation and lower expression of inflammatory factors than WT mice.16S rRNA gene sequencing demonstrated that CCL7 overexpression in intestinal epithelial cells improved HFD-induced gut microbial dysbiosis.Conclusions:Our study revealed that CCL7 overexpression in the intestinal epithelium protects mice against the progression of diet-induced obesity,hepatic steatosis,and enteric dysbiosis.

PLK1、CCL18在原发性肝癌中的表达及其与临床病理的关系

目的探讨Polo样激酶（Polo-like kinase 1,PLK1）、趋化因子配体18（Chemokine CC motif ligand18,CCL18）在原发性肝癌组织中的表达情况,分析PLK1、CCL18表达与肝癌患者临床病理特征的关系。方法 2009年2月~2010年12月于该院接受手术治疗的原发性肝癌患者60例,取肿瘤边缘处非坏死组织制作离体标本,采用免疫组化技术观察PLK1、CCL18的表达情况。结果 PLK1基因蛋白表达与癌栓、包膜是否完整、BCLC分期、Edmondson分级有关（P〈0.01）;病灶转移、肝硬化有关与CCL18基因蛋白表达有关（P〈0.05）;PLK1阳性表达与CCL18表达呈正相关（P〈0.05）。结论 PLK1、CCL18与肝癌病理特征密切相关,能够作为诊断、治疗的重要指标。

CCL18、MVD在乳腺癌组织中的表达及其与患者预后的关系研究

目的研究趋化因子配体18（CCLl8）与肿瘤微血管密度（MVD）在乳腺癌组织中表达水平及与患者预后的关系。方法收集2011年7月～2012年12月我院乳腺外科病理确诊为乳腺癌患者癌组织标本90例，癌旁组织标本30例及乳腺良性病变组织30例。应用免疫组化法检测CCLl8和MVD在3类组织中表达水平。结果CCL18在乳腺癌组织组的表达明显高于癌旁组织组和良性组织组（P=0．000）．并且乳腺癌的分期越晚CCLl8在乳腺癌组织组表达水平越高（P=0．000），乳腺癌组织组MVD的表达明显高于其余两组（P=0．000），且表达水平在Ⅲ期乳腺癌组织中明显高于Ⅰ期和Ⅱ期（P=0．000）。结论CCL18和MVD均可作为乳腺癌标志物之一，两者表达水平对于治疗和预后均有重要的意义。

趋化因子配体18在乳腺癌组织中的表达与预后分析

目的探讨趋化因子配体18在乳腺癌组织中的表达及其与乳腺癌患者预后的关系。方法入组病例的疾病诊断均以我院病理诊断为准并且均为女性患者,其中共有94例乳腺癌患者的组织标本,47例良性乳腺疾病患者的组织标本,对照组组织标本为良性乳腺病病灶周边的正常乳腺组织,共27例。采用免疫组化Envision方法,对标本检测CCL18、ER、PR、Her-2以及Ki-67等的表达。并对乳腺癌患者进行随访。结果在对照组、良性乳腺病组均未发现CCL18表达,在乳腺癌患者组中,CCL18的阳性表达率为67.02%(63/94);乳腺癌组CCL18的阳性表达率较对照组及良性乳腺疾病组显著升高(P<0.05)。在表达CCL18的63例乳腺癌患者中,CCL18的表达水平与肿瘤大小、淋巴结转移数目、临床分期,乳腺癌的分子类型以及ER、PR、Her-2的表达均有密切联系(P<0.05)。CCL18阳性乳腺癌患者的无病生存期(DFS)、总生存期(OS)均较CCL18阴性的乳腺癌患者的差(P<0.05)。结论 CCL18与乳腺癌的生物学特性密切相关,乳腺癌的一个重要的生物学指标,并且与乳腺患者的预后密切相关,可作为判断乳腺癌预后的一个重要参考指标进行研究。

CCL18在乳腺癌的表达及与患者预后的关系

目的:探讨趋化因子配体18(CCL18)在乳腺癌的表达及患者预后的关系。方法:收集2006年1月至2010年7月在本院乳腺外科病理确诊为乳腺癌患者94例,运用免疫组化检测CCL18在乳腺浸润性导管癌组织的表达,并对患者生存时间进行分析。结果:CCL18在远处转移组织的表达高于非远处转移组织(P<0.001),CCL18的表达与肿瘤组织学分级、肿瘤大小、淋巴结及远处转移情况有关(P<0.05)。CCL18低表达组患者有较高的无病生存率和总生存率(P<0.05)。结论:乳腺癌组织中CCL18高表达与乳腺癌预后相关,可作为乳腺癌恶性程度的预测指标。

COPD急性加重期的炎性指标临床研究

目的研究慢性阻塞性肺疾病急性发作期患者血清C反应蛋白(CRP)、趋化因子配体18(CCL18)含量变化及临床意义。方法检测30例COPD急性加重期、第7天和缓解期及30例体检者血清CRP、CCL18浓度,同时测定1 s用力呼气容积占预计值百分数(FEV1%pred)和动脉血氧分压(PaO2)。结果COPD急性加重期患者及缓解期血清CRP和CCL18水平较对照组均明显升高,有显著差异性(P<0.05);而治疗组缓解期血清CRP和CCL18水平均较急性发作期明显降低,具有统计学意义(P<0.01)。COPD患者CRP和CCL18水平与FEV1%pred、PaO2均呈直线负相关关系(P<0.05)。结论检测血清CRP和CCL18对COPD发生发展及疾病严重程度的判断,指导抗生素的使用有一定意义。

口腔黏膜CCLl8、E-cadherin蛋白与口腔鳞状细胞癌侵袭、转移的关系

目的 探讨口腔黏膜趋化因子配体18(chemokine cc-motif ligand 18,CCL18)、上皮细胞钙黏蛋白(Epithelial-cadherin,E-cadherin)蛋白与口腔鳞状细胞癌侵袭、转移的关系。方法 本研究选取2014年6月 2017年6月十堰市太和医院 收治的100例口腔鳞状细胞癌患者为研究对象。采用ELISA法测定其口腔癌旁正常组织、鳞癌组织中CCLl8、E-cadherin的 蛋白表达水平,并分析其与患者临床病理参数之间的关系。结果 口腔鳞状细胞癌患者鳞癌组织中CCL18表达水平明显高 于癌旁正常组织,E-cadherin表达水平明显低于癌旁正常组织且差异具有统计学意义(P<0.05)。随着肿瘤直径、分化程 度、临床分期的增加以及发生淋巴结转移,患者CCL18表达水平逐渐增加、E-cadherin表达水平逐渐降低,且差异具有统 计学意义(P<0.05)。结论 CCL18与E-cadherin在口腔鳞癌患者肿瘤组织均存在异常表达,且表达水平与患者临床分 期、淋巴结转移状态密切相关,提示二者参与口腔鳞状细胞癌的发生与发展。

Transforming growth factor-β and toll-like receptor-4 polymorphisms are not associated with fibrosis in haemochromatosis

AIM:To investigate the role of genetic polymorphisms in the progression of hepatic fibrosis in hereditary haemochromatosis.METHODS:A cohort of 245 well-characterised C282Y homozygous patients with haemochromatosis was studied,with all subjects having liver biopsy data and DNA available for testing.This study assessed the association of eight single nucleotide polymorphisms(SNPs)in a total of six genes including toll-like receptor 4(TLR4),transforming growth factor-beta(TGF-β),oxoguanine DNA glycosylase,monocyte chemoattractant protein 1,chemokine C-C motif receptor 2 and interleukin-10 with liver disease severity.Genotyping was performed using high resolution melt analysis and sequencing.The results were analysed in relation to the stage of hepatic fibrosis in multivariate analysis incorporating other cofactors including alcohol consumption and hepatic iron concentration.RESULTS:There were significant associations between the cofactors of male gender(P=0.0001),increasing age(P=0.006),alcohol consumption(P=0.0001),steatosis(P=0.03),hepatic iron concentration(P<0.0001)and the presence of hepatic fibrosis.Of the candidate gene polymorphisms studied,none showed a significant association with hepatic fibrosis in univariate or multivariate analysis incorporating cofactors.We also specifically studied patients with hepatic iron loading above threshold levels for cirrhosis and compared the genetic polymorphisms between those with no fibrosis vs cirrhosis however there was no significant effect from any of the candidate genes studied.Importantly,in this large,well characterised cohort of patients there was no association between SNPs for TGF-βor TLR4and the presence of fibrosis,cirrhosis or increasing fibrosis stage in multivariate analysis.CONCLUSION:In our large,well characterised group of haemochromatosis subjects we did not demonstrate any relationship between candidate gene polymorphisms and hepatic fibrosis or cirrhosis.

Neuroinflammation in mild respiratory COVID‑19:insights into cognitive impairment in milder cases

Severe acute respiratory syndrome coronavirus 2(SARSCoV-2)infection has been extensively shown to cause many neurological sequelae,and cognitive deficits(known as“brain fog”)may particularly and widely occur even in individuals with mild symptoms[1].Peripheral hyperinflammation as well as central nervous system(CNS)local immune responses may synergistically contribute to brain autoimmune injury.In addition to the direct neuroinvasion of SARS-CoV-2 and nonimmune effects such as severe systemic hypoxemia and vascular thrombosis,the central mechanism by which SARSCoV-2 accelerates cognitive-related symptoms may be related to immune effects[2].However,the precise neuroinflammatory mechanisms of SARS-CoV-2 infection have not been fully established.Fernández-Casta-da et al.[3]provided direct evidence and unique insights into the potential mechanism of cognitive impairment in mild respiratory coronavirus disease 2019(COVID-19)cases.

参芪扶正联合化疗对乳腺癌患者血清TNF-α,CCL18及IL-6表达水平的影响

目的:探讨TNF-α,CCL18及IL-6在乳腺癌患者血清中表达的临床意义及3个因子的相关性,并评估参芪扶正注射液联合化疗在治疗乳腺癌患者过程中的价值。方法:采用ELISA法检测46例乳腺癌患者,23例乳腺良性病和19例健康体检者血清TNF-α,CCL18及IL-6水平,并比较对照组和实验组用药前后血清表达水平的变化和疗效。结果:TNF-α,CCL18及IL-6在健康体检者组,乳腺良性病组和乳腺癌组血清中表达水平依次升高,差异有统计学意义(均P<0.05);TNF-α,CCL18及IL-6的表达水平与淋巴结转移和ER状态相关,而与PR,HER-2,肿瘤大小和病理类型等无关;乳腺癌患者血清中TNF-α,CCL18及IL-6表达水平呈正相关;参芪扶正注射液联合化疗能降低三者表达水平,差异具有统计学意义(P<0.05);实验组治疗有效率高于对照组。结论:高水平的TNF-α,CCL18及IL-6可能协同促进了乳腺癌的发生和发展,检测这3个因子的表达有助于乳腺良恶性的鉴别;参芪扶正注射液联合化疗能保护骨髓和减轻化疗毒副作用,并能降低三者血清表达水平,在调节乳腺癌患者免疫力方面起着积极的作用。

Transferrin receptor-targeted immunostimulant for photodynamic immunotherapy against metastatic tumors through β-catenin/CREB interruption

The immunosuppressive phenotype of tumor cells extensively attenuates the immune activation effects of traditional treatments.In this work,a transferrin receptor(TfR)targeted immunostimulant(PTI)is fabricated for photodynamic immunotherapy against metastatic tumors by interrupting β-catenin signal pathway.To synthesize PTI,the photosensitizer conjugated TfR targeting peptide moiety(Palmitic-K(PpIX)-HAIYPRH)is unitized to encapsulate the transcription interrupter of ICG-001.On the one hand,the recognition of PTI and TfR can promote drug delivery into tumor cells to destruct primary tumors through photodynamic therapy and initiate an immunogenic cell death with the release of tumorassociated antigens.On the other hand,PTI will interrupt the binding between b-catenin andcAMP response element-binding protein(CREB),regulating the gene transcription to downregulate programmed death ligand 1(PD-L1)while upregulating CeC motif chemokine ligand 4(CCL4).Furthermore,the elevated CCL4 can recruit the dendritic cells to present tumor-specific antigens and promote T cells activation and infiltration,and the downregulated PD-L1 can avoid the immune evasion of tumor cells and activate systemic anti-tumor immunity to eradicate lung metastasis.This work may inspire the development of antibody antibody-free strategy to activate systemic immune response in consideration of immunosuppressive conditions.

Spinal CCL2 Promotes Central Sensitization, Long-Term Potentiation, and Inflammatory Pain via CCR2： Further Insights into Molecular, Synaptic, and Cellular Mechanisms

Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 （C-C motif chemokine ligand 2） has been shown to enhance N-methyl-D-aspartate （NMDA）-induced currents in spinal outer lamina II （Iio） neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expres- sion in excitatory vesicular glutamate transporter subtype 2-positive （VGLUT2＋） neurons. CCL2 increased NMDA- induced currents in CCR2＋/VGLUT2＋ neurons in lamina IIo; it also enhanced the synaptic NMDA currents evoked by dorsal root stimulation; and furthermore, it increased the total and synaptic NMDA currents in somatostatin- expressing excitatory neurons. Finally, intrathecal RS504393 reversed the long-term potentiation evoked in the spinal cord by C-fiber stimulation. Our findings suggest that CCL2 directly modulates synaptic plasticity in CCR2- expressing excitatory neurons in spinal lamina Iio, and this underlies the generation of central sensitization in patho- logical pain.

Spinal CCL2 Promotes Pain Sensitization by Rapid Enhancement of NMDA-Induced Currents Through the ERK-GluN2B Pathway in Mouse Lamina Ⅱ Neurons

Previous studies have shown that CCL2(C-C motif chemokine ligand 2)induces chronic pain,but the exact mechanisms are still unknown.Here,we established models to explore the potential mechanisms.Behavioral experiments revealed that an antagonist of extracellular signal-regulated kinase(ERK)inhibited not only CCL2-induced inflammatory pain,but also pain responses induced by complete Freund’s adjuvant.We posed the question of the intracellular signaling cascade involved.Subsequent experiments showed that CCL2 up-regulated the expression of phosphorylated ERK(pERK)and N-methyl D-aspartate receptor[NMDAR]subtype 2B(GluN2B);meanwhile,antagonists of CCR2 and ERK effectively reversed these phenomena.Whole-cell patchclamp recordings revealed that CCL2 enhanced the NMDAR-induced currents via activating the pERK pathway,which was blocked by antagonists of GluN2B and ERK.In summary,we demonstrate that CCL2 directly interacts with CCR2 to enhance NMDAR-induced currents,eventually leading to inflammatory pain mainly through the CCL2-CCR2-pERK-GluN2B pathway.

Functional roles of CCL5/RANTES in liver disease

Inflammation,which is mediated by leukocyte trafficking and activation,plays a prominent role in the pathogenesis of acute and chronic liver injury.Chemokines are critical mediators involved in the migration of leukocytes into the diseased liver via binding to their G protein-coupled receptors.CeC motif ligand 5(CCL5)belongs to the CC-chemokine family and is secreted by several hepatic cell pop-ulations including hepatocytes,macrophages,hepatic stellate cells,and endothelial cells upon activation.CCL5 regulates the recruitment and migration of T cells(via CCR5)and NK cells(via CCR1).Moreover,CCL5 activates and stimulates T cell proliferation and cytokine production,sequentially regulating in-flammatory responses.Accumulating studies have identified crucial effects of CCL5 both in liver-disease patients and in experimental models,in which CCL5 is elevated and displays distinct effects according to pathological conditions.In this review,we discussed the crucial functions of CCL5 in liver diseases,including acute liver failure,hepatic ischemia-reperfusion injury,acute liver failure,acute and viral hepatitis,alcoholic liver disease,non-alcoholic fatty liver disease,fibrosis,and hepatocellular carcinoma.Continued understanding the roles of CCL5 in liver disease and their mechanisms of activation are indispensable for the development of effective clinical therapeutics.