title: Toll-like Receptor 4 Signaling on Dendritic Cells Suppresses Polymorphonuclear Leukocyte CXCR2 Expression and Trafficking via Interleukin 10 During Intra-abdominal Sepsis.
abstract: BACKGROUND
  Toll-like receptor 4 (TLR4) is a critical receptor involved in the sensing of gram-negative bacterial infection. However, the roles of TLR4 in sepsis are cell-type specific. Dendritic cells (DCs) are known to play a central role in microbial detection, alerting the immune system to the presence of infection and coordinating adaptive immune response. The goal of this study was to investigate the impact of DC-specific TLR4 signaling on host defense against intra-abdominal polymicrobial sepsis.
  
  
  METHODS
  C57BL/6, global Tlr4 knockout, cell-specific knockout control, and CD11c-specific Tlr4(-/-) mice underwent cecal ligation and puncture (CLP).
  
  
  RESULTS
  Specific deletion of TLR4 on DCs in mice improved survival and enhanced bacterial clearance. Deletion of TLR4 on DCs was associated with lower levels of circulating interleukin 10 (IL-10), higher polymorphonuclear leukocyte (PMN) accumulation in the peritoneal cavity, and higher expression of chemokine (C-X-C motif) receptor 2 (CXCR2) on PMNs after CLP. In vitro studies of DC and neutrophil cocultures confirmed that TLR4-dependent secretion of IL-10 from DCs regulated neutrophil CXCR2 expression.
  
  
  CONCLUSIONS
  Our data shed light on a previously unrecognized role for TLR4 signaling on DCs in driving IL-10 secretion during sepsis and, through this pathway, regulates PMN recruitment via suppression of CXCR2 expression.
authors.affiliation: Department of Surgery, University of Pittsburgh, Pennsylvania.
authors.forename: Meihong
authors.initials: M
authors.lastname: Deng
authors.affiliation: Department of General Surgery, Tianjin Medical University General Hospital.
authors.forename: Tao
authors.initials: T
authors.lastname: Ma
authors.affiliation: Department of Pathophysiology, Southern Medical University, Guangzhou, China.
authors.forename: Zhengzheng
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Department of Surgery, University of Pittsburgh, Pennsylvania.
authors.forename: Kent R
authors.initials: KR
authors.lastname: Zettel
authors.affiliation: Department of Surgery, University of Pittsburgh, Pennsylvania.
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Scott
authors.affiliation: Department of Surgery, University of Pittsburgh, Pennsylvania.
authors.forename: Hong
authors.initials: H
authors.lastname: Liao
authors.affiliation: Department of Surgery, University of Pittsburgh, Pennsylvania.
authors.forename: Alicia
authors.initials: A
authors.lastname: Frank
authors.affiliation: Department of Surgery, University of Pittsburgh, Pennsylvania.
authors.forename: Adrian E
authors.initials: AE
authors.lastname: Morelli
authors.affiliation: Johns Hopkins Children's Center, Baltimore, Maryland.
authors.forename: Chhinder P
authors.initials: CP
authors.lastname: Sodhi
authors.affiliation: Johns Hopkins Children's Center, Baltimore, Maryland.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hackam
authors.affiliation: Department of Surgery, University of Pittsburgh, Pennsylvania.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000378:metabolism*; D004195:Disease Models, Animal; D016753:Interleukin-10 / Q000378:metabolism*; D059413:Intraabdominal Infections / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D018805:Sepsis / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D023063:Receptors, Interleukin-8B; D051197:Toll-Like Receptor 4; D016753:Interleukin-10
keywords: CLP; CXCR2; IL-10; PMN recruitment; TLR4; dendritic cell; sepsis