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J Infect Dis. 2016 Apr 15;213(8):1280-8. doi: 10.1093/infdis/jiv562. Epub 2015 Nov 24.

Toll-like Receptor 4 Signaling on Dendritic Cells Suppresses Polymorphonuclear Leukocyte CXCR2 Expression and Trafficking via Interleukin 10 During Intra-abdominal Sepsis.

Author information

1
Department of Surgery, University of Pittsburgh, Pennsylvania.
2
Department of General Surgery, Tianjin Medical University General Hospital.
3
Department of Pathophysiology, Southern Medical University, Guangzhou, China.
4
Johns Hopkins Children's Center, Baltimore, Maryland.

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.

KEYWORDS:

CLP; CXCR2; IL-10; PMN recruitment; TLR4; dendritic cell; sepsis

PMID:
26603204
PMCID:
PMC4799664
DOI:
10.1093/infdis/jiv562
[Indexed for MEDLINE]
Free PMC Article

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