CCR 2 dependent neutrophil activation and mobilization rely on TLR 4p 38 axis during liver ischemia-reperfusion injury

Liver ischemia-reperfusion injury (IRI) is a common clinical problem in which neutrophil recruitment is an essential event. Our previous study revealed the important role of C-C motif chemokine receptor 2 (CCR2) in neutrophils during liver IRI. The aim of the present study was to further investigate the underlying mechanisms mediating the changes in CCR2 expression in neutrophils during this pathophysiological process. Herein, we found that TLR4 ablation reduced neutrophil mobilization from the bone marrow and the subsequent infiltration into the liver during liver IRI; neutrophil-derived CCR2 expression was also repressed. In addition, neutrophil mobilization was dependent on CCR2 expression in neutrophils, which in turn relied on activation of the TLR4-p38 axis during liver IRI. In conclusion, neutrophil-derived CCR2 expression regulates neutrophil mobilization from the bone marrow and infiltration into the liver, which requires activation of the TLR4-p38 axis during liver IRI.

[1]  T. Luedde,et al.  Chemokine (C‐C motif) receptor 2–positive monocytes aggravate the early phase of acetaminophen‐induced acute liver injury , 2016, Hepatology.

[2]  A. Xu,et al.  Lipocalin-2 mediates non-alcoholic steatohepatitis by promoting neutrophil-macrophage crosstalk via the induction of CXCR2. , 2016, Journal of hepatology.

[3]  Y. Wang,et al.  Berberine in combination with yohimbine attenuates sepsis-induced neutrophil tissue infiltration and multiorgan dysfunction partly via IL-10-mediated inhibition of CCR2 expression in neutrophils. , 2016, International immunopharmacology.

[4]  Ping Wang,et al.  Role of reverse transendothelial migration of neutrophils in inflammation , 2016, Biological chemistry.

[5]  S. Gemma,et al.  The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation , 2016, Mediators of inflammation.

[6]  T. Billiar,et al.  CCL2-CCR2 signaling promotes hepatic ischemia/reperfusion injury. , 2016, The Journal of surgical research.

[7]  A. Mansell,et al.  Toll-like receptors: the swiss army knife of immunity and vaccine development , 2016, Clinical & translational immunology.

[8]  X. Yao,et al.  IRE1-RACK1 axis orchestrates ER stress preconditioning-elicited cytoprotection from ischemia/reperfusion injury in liver. , 2016, Journal of molecular cell biology.

[9]  K. Man,et al.  Repressor and activator protein accelerates hepatic ischemia reperfusion injury by promoting neutrophil inflammatory response , 2016, Oncotarget.

[10]  Sooyeon Lee,et al.  Mitochondrial Dysfunction and Autophagy in Hepatic Ischemia/Reperfusion Injury , 2015, BioMed research international.

[11]  T. Billiar,et al.  Damage‐associated molecular pattern–activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury , 2015, Hepatology.

[12]  F. Cunha,et al.  CCR2 Expression in Neutrophils Plays a Critical Role in Their Migration Into the Joints in Rheumatoid Arthritis , 2015, Arthritis & rheumatology.

[13]  M. Huang,et al.  Estrogen Sulfotransferase Is an Oxidative Stress-responsive Gene That Gender-specifically Affects Liver Ischemia/Reperfusion Injury* , 2015, The Journal of Biological Chemistry.

[14]  J. Verheij,et al.  Solutions to the discrepancies in the extent of liver damage following ischemia/reperfusion in standard mouse models. , 2015, Journal of hepatology.

[15]  Jungang Xie,et al.  CCL2/CCR2-Dependent Recruitment of Th17 Cells but Not Tc17 Cells to the Lung in a Murine Asthma Model , 2015, International Archives of Allergy and Immunology.

[16]  R. Sun,et al.  Infiltrating neutrophils aggravate metabolic liver failure in fah‐deficient mice , 2015, Liver international : official journal of the International Association for the Study of the Liver.

[17]  V. Kuchroo,et al.  T‐cell immunoglobulin and mucin domain 4 (TIM‐4) signaling in innate immune‐mediated liver ischemia‐reperfusion injury , 2014, Hepatology.

[18]  I. Dontas,et al.  Rodent models of hepatic ischemia-reperfusion injury: time and percentage-related pathophysiological mechanisms. , 2014, The Journal of surgical research.

[19]  Jinxiang Zhang,et al.  Toll-Like Receptor 4 in Bone Marrow-Derived Cells Contributes to the Progression of Diabetic Retinopathy , 2014, Mediators of inflammation.

[20]  T. Arumugam,et al.  Role of CCR2 in Inflammatory Conditions of the Central Nervous System , 2014, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[21]  A. Doerfler,et al.  Ischemia/reperfusion during normothermic perfusion. , 2014, Progres en urologie : journal de l'Association francaise d'urologie et de la Societe francaise d'urologie.

[22]  S. K. Park,et al.  Effect of gender differences on the regulation of renal ischemia-reperfusion-induced inflammation in mice , 2014, Molecular medicine reports.

[23]  Y. Vodovotz,et al.  Roles of dendritic cells in murine hepatic warm and liver transplantation‐induced cold ischemia/reperfusion injury , 2013, Hepatology.

[24]  Guo‐Liang Wang,et al.  Hepatocellular carcinoma and macrophage interaction induced tumor immunosuppression via Treg requires TLR4 signaling. , 2012, World journal of gastroenterology.

[25]  F. S. Ramalho,et al.  The Current State of Knowledge of Hepatic Ischemia-Reperfusion Injury Based on Its Study in Experimental Models , 2012, Journal of biomedicine & biotechnology.

[26]  A. Luster,et al.  Neutrophils cascading their way to inflammation. , 2011, Trends in immunology.

[27]  C. Esmon,et al.  Endogenous Histones Function as Alarmins in Sterile Inflammatory Liver Injury Through Toll-like Receptor 9 in Mice , 2011, Hepatology.

[28]  D. Kim,et al.  CD44 Disruption Attenuates Murine Hepatic Ischemia/Reperfusion Injury , 2011, Journal of Korean medical science.

[29]  S. Uemoto,et al.  Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate Hepatic Ischemia Reperfusion Injury in a Rat Model , 2011, PloS one.

[30]  F. Cunha,et al.  Essential role of CCR2 in neutrophil tissue infiltration and multiple organ dysfunction in sepsis. , 2011, American journal of respiratory and critical care medicine.

[31]  E. Murphy,et al.  Estrogen receptor activation and cardioprotection in ischemia reperfusion injury. , 2010, Trends in cardiovascular medicine.

[32]  C. Bai,et al.  Roles of CC chemokine receptors (CCRs) on lipopolysaccharide-induced acute lung injury , 2010, Respiratory Physiology & Neurobiology.

[33]  G. Plitas,et al.  Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion. , 2010, Journal of Clinical Investigation.

[34]  Zhang Jinxiang,et al.  Bone marrow and non-bone marrow TLR4 regulates hepatic ischemia/reperfusion injury. , 2009, Biochemical and biophysical research communications.

[35]  Mauro M. Teixeira,et al.  Regulation of chemokine receptor by Toll-like receptor 2 is critical to neutrophil migration and resistance to polymicrobial sepsis , 2009, Proceedings of the National Academy of Sciences.

[36]  F. Cunha,et al.  Toll-like receptor 4 signaling leads to neutrophil migration impairment in polymicrobial sepsis* , 2006, Critical care medicine.

[37]  K. Tracey,et al.  The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion , 2005, The Journal of experimental medicine.

[38]  S. Dower,et al.  Toll-Like Receptor (TLR)2 and TLR4 Agonists Regulate CCR Expression in Human Monocytic Cells1 , 2004, The Journal of Immunology.

[39]  S. Foster,et al.  Selective Roles for Toll-Like Receptor (TLR)2 and TLR4 in the Regulation of Neutrophil Activation and Life Span1 , 2003, The Journal of Immunology.

[40]  Lu Gao,et al.  Targeting TRAF3 signaling protects against hepatic ischemia/reperfusions injury. , 2016, Journal of hepatology.

[41]  N. Németh,et al.  Hemorheological changes in ischemia-reperfusion: an overview on our experimental surgical data. , 2014, Clinical hemorheology and microcirculation.

[42]  G. Barritt,et al.  Evidence that estrogen receptors play a limited role in mediating enhanced recovery of bile flow in female rats in the acute phase of liver ischemia reperfusion injury. , 2013, Annals of hepatology.