title: CXCL1 can be regulated by IL-6 and promotes granulocyte adhesion to brain capillaries during bacterial toxin exposure and encephalomyelitis.
abstract: BACKGROUND
  Granulocytes generally exert protective roles in the central nervous system (CNS), but recent studies suggest that they can be detrimental in experimental autoimmune encephalomyelitis (EAE), the most common model of multiple sclerosis. While the cytokines and adhesion molecules involved in granulocyte adhesion to the brain vasculature have started to be elucidated, the required chemokines remain undetermined.
  
  
  METHODS
  CXCR2 ligand expression was examined in the CNS of mice suffering from EAE or exposed to bacterial toxins by quantitative RT-PCR and in situ hybridization. CXCL1 expression was analyzed in IL-6-treated endothelial cell cultures by quantitative RT-PCR and ELISA. Granulocytes were counted in the brain vasculature after treatment with a neutralizing anti-CXCL1 antibody using stereological techniques.
  
  
  RESULTS
  CXCL1 was the most highly expressed ligand of the granulocyte receptor CXCR2 in the CNS of mice subjected to EAE or infused with lipopolysaccharide (LPS) or pertussis toxin (PTX), the latter being commonly used to induce EAE. IL-6 upregulated CXCL1 expression in brain endothelial cells by acting transcriptionally and mediated the stimulatory effect of PTX on CXCL1 expression. The anti-CXCL1 antibody reduced granulocyte adhesion to brain capillaries in the three conditions under study. Importantly, it attenuated EAE severity when given daily for a week during the effector phase of the disease.
  
  
  CONCLUSIONS
  This study identifies CXCL1 not only as a key regulator of granulocyte recruitment into the CNS, but also as a new potential target for the treatment of neuroinflammatory diseases such as multiple sclerosis.
authors.affiliation: Department of Endocrinology and Genomics, Laval University Hospital Research Center, 2705 Laurier Boulevard, Quebec G1V 4G2, QC, Canada.
authors.forename: Monica
authors.initials: M
authors.lastname: Roy
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Richard
authors.forename: Aline
authors.initials: A
authors.lastname: Dumas
authors.forename: Luc
authors.initials: L
authors.lastname: Vallières
mesh_terms: D000818:Animals; D000906:Antibodies; D057134:Antibodies, Neutralizing / Q000627:therapeutic use; D015703:Antigens, CD / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D054426:Chemokine CXCL2 / Q000276:immunology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000473:pathology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006098:Granulocytes / Q000187:drug effects / Q000502:physiology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000172:deficiency / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology*; D023063:Receptors, Interleukin-8B / Q000276:immunology
chemical_list: C100745:Aif1 protein, rat; D000906:Antibodies; D057134:Antibodies, Neutralizing; D015703:Antigens, CD; D002135:Calcium-Binding Proteins; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C513297:Cxcl1 protein, rat; C513296:Cxcl2 protein, rat; D005904:Glial Fibrillary Acidic Protein; D015850:Interleukin-6; D008840:Microfilament Proteins; D023063:Receptors, Interleukin-8B; D018799:Intercellular Adhesion Molecule-1; D037342:Pertussis Toxin