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 leukoc...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.展开更多
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...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.展开更多
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...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.展开更多
Objective Despite accumulating evidence on a role of immune cells and their associated chemicals in mecha- nisms of pain, few studies have addressed the potential role of chemokines in the descending facilitation of p...Objective Despite accumulating evidence on a role of immune cells and their associated chemicals in mecha- nisms of pain, few studies have addressed the potential role of chemokines in the descending facilitation of persistent pain. The present study was undertaken to test the hypothesis that the chemokine （C-C motif） ligand 2 （CCL2） （commonly known as monocyte chemoattractant protein-1） signaling in the rostral ventromedial medulla （RVM）, a pivotal structure in brainstem pain modulatory circuitry, is involved in descending pain facilitation in rats. Methods An L5 spinal nerve ligation （SNL） was produced in rats under pentobarbital anesthesia. Western blot and immunohistochemistry were used to detect the expression levels of CCL2 and CCL2 receptor （CCR2）, and examine their distributions compared with the neuronal marker NeuN as well as glial markers glial fibrillary acidic protein （GFAP, astroglial） and CD 11 b （microglial）, respectively. Results SNL induced an increase in CCL2 expression in the RVM, and this returned to the control level at 4 weeks after injury. The induced CCL2 colocalized with NeuN, but not with GFAP and CD1 lb. CCR2 was also upregu- lated by SNL in the RVM, and this increase lasted for at least 4 weeks. CCR2 was colocalized with CD1 lb but not GFAP. Few RVM neurons also exhibited CCR2 staining. Neutralizing CCL2 with an anti-CCL2 antibody （0.2-20 ng） or injecting RS-102895 （0.1-10 pmol）, a CCR2b chemokine receptor antagonist, into the RVM on day 1 after SNL, significantly at- tenuated the established thermal and mechanical hypersensitivity. In addition, injection of recombinant rat CCL2 （0.03-3 pmol） into the RVM induced dose-dependent hyperalgesia, which was prevented by pretreatment with RS-102895 （10 pmol）. Interleukin-β （IL-1]3）, a potent inducer of neuronal CCL2, was also selectively upregulated in RVM reactive as- trocytes. Injection of IL-1 ]3 （120 fmol） into the RVM induced behavioral hyperalgesia, which was blocked by RS-102895 （10 pmol）. However, an IL-1 receptor antagonist （3 pmol） did not prevent CCL2 （3 pmol）-induced hyperalgesia. These results suggest that the effect of CCL2 is downstream to IL-113 signaling. Conclusion The IL-1 β and CCL2-CCR2 signaling cascades play a role in neuron-glia-cytokine interactions and the descending facilitation of neuropathic pain.展开更多
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 epithel...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.展开更多
We previously showed that hydrogen sulfide(H2S)has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice.However,the precise mechanism underlying the role of H2S in this situation r...We previously showed that hydrogen sulfide(H2S)has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice.However,the precise mechanism underlying the role of H2S in this situation remains unclear.In this study,we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine,a H2S precursor,attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionineβsynthase(a major H2S synthetase in the brain)in the prefrontal cortex.We also found that an miR-9-5p inhibitor blocked the expression of cystathionineβsynthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia.Furthermore,miR-9-5p overexpression increased cystathionine-β-synthase and H2S expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury.L-cysteine decreased the expression of CXCL11,an miR-9-5p target gene,in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3,FSTL1,SOCS2 and SOCS5,while treatment with an miR-9-5p inhibitor reversed these changes.These findings suggest that H2S can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoringβ-synthase expression,thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.展开更多
基金supported by the China Postdoctoral Science Foundation,No.2020M681689(to YMH)the Basic Scientific Research Projects of Nantong,Nos.JC2020015(to HX)and JC2020041(to YMH)。
文摘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.
基金This work was supported by grants from the National Science and Technology Major Project of China[2017ZX10203205]the National Natural Science Funds for Distinguished Young Scholar of China[81625003]+2 种基金Projects of Medical and Health Technology Program in Zhejiang Province[WKJ-ZJ-1514]China Postdoctoral Science Foundation[2017M612014]Zhejiang Medical and Technological Program[2018263185].
文摘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.
基金supported by the National Natural Science Foundation of China(Key Program),No.11932013the National Natural Science Foundation of China(General Program),No.82272255+2 种基金Armed Police Force High-Level Science and Technology Personnel ProjectThe Armed Police Force Focuses on Supporting Scientific and Technological Innovation TeamsKey Project of Tianjin Science and Technology Plan,No.20JCZDJC00570(all to XC)。
文摘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.
基金supported by grants from the National Institutes of Health (NS059028,NS060735, DE011964, DE021804, and DE018573)
文摘Objective Despite accumulating evidence on a role of immune cells and their associated chemicals in mecha- nisms of pain, few studies have addressed the potential role of chemokines in the descending facilitation of persistent pain. The present study was undertaken to test the hypothesis that the chemokine （C-C motif） ligand 2 （CCL2） （commonly known as monocyte chemoattractant protein-1） signaling in the rostral ventromedial medulla （RVM）, a pivotal structure in brainstem pain modulatory circuitry, is involved in descending pain facilitation in rats. Methods An L5 spinal nerve ligation （SNL） was produced in rats under pentobarbital anesthesia. Western blot and immunohistochemistry were used to detect the expression levels of CCL2 and CCL2 receptor （CCR2）, and examine their distributions compared with the neuronal marker NeuN as well as glial markers glial fibrillary acidic protein （GFAP, astroglial） and CD 11 b （microglial）, respectively. Results SNL induced an increase in CCL2 expression in the RVM, and this returned to the control level at 4 weeks after injury. The induced CCL2 colocalized with NeuN, but not with GFAP and CD1 lb. CCR2 was also upregu- lated by SNL in the RVM, and this increase lasted for at least 4 weeks. CCR2 was colocalized with CD1 lb but not GFAP. Few RVM neurons also exhibited CCR2 staining. Neutralizing CCL2 with an anti-CCL2 antibody （0.2-20 ng） or injecting RS-102895 （0.1-10 pmol）, a CCR2b chemokine receptor antagonist, into the RVM on day 1 after SNL, significantly at- tenuated the established thermal and mechanical hypersensitivity. In addition, injection of recombinant rat CCL2 （0.03-3 pmol） into the RVM induced dose-dependent hyperalgesia, which was prevented by pretreatment with RS-102895 （10 pmol）. Interleukin-β （IL-1]3）, a potent inducer of neuronal CCL2, was also selectively upregulated in RVM reactive as- trocytes. Injection of IL-1 ]3 （120 fmol） into the RVM induced behavioral hyperalgesia, which was blocked by RS-102895 （10 pmol）. However, an IL-1 receptor antagonist （3 pmol） did not prevent CCL2 （3 pmol）-induced hyperalgesia. These results suggest that the effect of CCL2 is downstream to IL-113 signaling. Conclusion The IL-1 β and CCL2-CCR2 signaling cascades play a role in neuron-glia-cytokine interactions and the descending facilitation of neuropathic pain.
基金a grant from the Natural Science Funds for Distinguished Young Scholar of Guangdong Province(No.2016A030306043).
文摘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.
基金supported by the National Natural Science Foundation of China,Nos.82271327(to ZW),82072535(to ZW),81873768(to ZW),and 82001253(to TL).
文摘We previously showed that hydrogen sulfide(H2S)has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice.However,the precise mechanism underlying the role of H2S in this situation remains unclear.In this study,we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine,a H2S precursor,attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionineβsynthase(a major H2S synthetase in the brain)in the prefrontal cortex.We also found that an miR-9-5p inhibitor blocked the expression of cystathionineβsynthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia.Furthermore,miR-9-5p overexpression increased cystathionine-β-synthase and H2S expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury.L-cysteine decreased the expression of CXCL11,an miR-9-5p target gene,in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3,FSTL1,SOCS2 and SOCS5,while treatment with an miR-9-5p inhibitor reversed these changes.These findings suggest that H2S can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoringβ-synthase expression,thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.
