Defective Innate Immunity Predisposes Murine Neonates to Poor Sepsis Outcome but is Reversed by TLR Agonists

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2008 Jul 2

PMID 18591384

Citations 108

Authors

James L Wynn

Philip O Scumpia

Robert D Winfield

Matthew J Delano

Kindra Kelly-Scumpia

Tolga Barker

Ricardo Ungaro

Ofer Levy

Lyle L Moldawer

Affiliations

Soon will be listed here.

Abstract

Neonates exhibit an increased risk of sepsis mortality compared with adults. We show that in contrast to adults, survival from polymicrobial sepsis in murine neonates does not depend on an intact adaptive immune system and is not improved by T cell-directed adaptive immunotherapy. Furthermore, neonates manifest an attenuated inflammatory and innate response to sepsis, and have functional defects in their peritoneal CD11b(+) cells. Activation of innate immunity with either a Toll-like receptor 4 (TLR4) or TLR7/8 agonist, but not a TLR3 agonist, increased the magnitude, but abbreviated the early systemic inflammatory response, reduced bacteremia, and improved survival to polymicrobial sepsis. TLR4 agonist pretreatment enhanced peritoneal neutrophil recruitment with increased oxidative burst production, whereas the TLR7/8 agonist also enhanced peritoneal neutrophil recruitment with increased phagocytic ability. These benefits were independent of the adaptive immune system and type I interferon signaling. Improving innate immune function with select TLR agonists may be a useful strategy to prevent neonatal sepsis mortality.

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