title: Regulation of chemokine receptor by Toll-like receptor 2 is critical to neutrophil migration and resistance to polymicrobial sepsis.
abstract: Patients with sepsis have a marked defect in neutrophil migration. Here we identify a key role of Toll-like receptor 2 (TLR2) in the regulation of neutrophil migration and resistance during polymicrobial sepsis. We found that the expression of the chemokine receptor CXCR2 was dramatically down-regulated in circulating neutrophils from WT mice with severe sepsis, which correlates with reduced chemotaxis to CXCL2 in vitro and impaired migration into an infectious focus in vivo. TLR2 deficiency prevented the down-regulation of CXCR2 and failure of neutrophil migration. Moreover, TLR2(-/-) mice exhibited higher bacterial clearance, lower serum inflammatory cytokines, and improved survival rate during severe sepsis compared with WT mice. In vitro, the TLR2 agonist lipoteichoic acid (LTA) down-regulated CXCR2 expression and markedly inhibited the neutrophil chemotaxis and actin polymerization induced by CXCL2. Moreover, neutrophils activated ex vivo by LTA and adoptively transferred into naïve WT recipient mice displayed a significantly reduced competence to migrate toward thioglycolate-induced peritonitis. Finally, LTA enhanced the expression of G protein-coupled receptor kinases 2 (GRK2) in neutrophils; increased expression of GRK2 was seen in blood neutrophils from WT mice, but not TLR2(-/-) mice, with severe sepsis. Our findings identify an unexpected detrimental role of TLR2 in polymicrobial sepsis and suggest that inhibition of TLR2 signaling may improve survival from sepsis.
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, University of Säo Paulo, 14049-900 Ribeirão Preto, Brazil. jcafilho@usp.br
authors.forename: Jose C
authors.initials: JC
authors.lastname: Alves-Filho
authors.forename: Andressa
authors.initials: A
authors.lastname: Freitas
authors.forename: Fabricio O
authors.initials: FO
authors.lastname: Souto
authors.forename: Fernando
authors.initials: F
authors.lastname: Spiller
authors.forename: Heitor
authors.initials: H
authors.lastname: Paula-Neto
authors.forename: Joao S
authors.initials: JS
authors.lastname: Silva
authors.forename: Ricardo T
authors.initials: RT
authors.lastname: Gazzinelli
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Ferreira
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007113:Immunity, Innate / Q000187:drug effects; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D010538:Peritonitis / Q000150:complications; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000150:complications / Q000276:immunology* / Q000382:microbiology*; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D013682:Teichoic Acids / Q000008:administration & dosage / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000172:deficiency / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D023063:Receptors, Interleukin-8B; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; C009900:lipoteichoic acid; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2