Abstract
In a mouse model of Escherichia coli sepsis characterized by a primary peritoneal infection with 10(4) E. coli and a gradually growing bacterial load, we here show that the early cytokine response and antibacterial defense are dominated by TLR4 via a cooperative action of MyD88 and Trif. Although MyD88(-/-) mice succumbed earlier than WT mice in this E. coli peritonitis model, Trif(-/-) mice displayed a small but significant survival advantage. Despite a large early deficit in antimicrobial defense, TLR4(-/-) mice showed an unaltered survival with normal neutrophil attraction to the peritoneal cavity and normal or even elevated late cytokine release. TLR2 compensated for the lack of TLR4 because TLR2(-/-)/TLR4(-/-) mice did show decreased neutrophil attraction and increased mortality compared with WT mice. Nearly normal early peritoneal TNFα production and lack of early counterregulating systemic levels of the chemoattractant KC were associated with normal peritoneal neutrophil attraction in TLR4(-/-) mice. Late stage increased TNF, IL-1β, IFN-β, and typical IFN-γ production in TLR4(-/-) mice prompted us to evaluate expression of the negative feedback regulator SOCS-1. Lack of early hepatic SOCS-1 expression in TLR4(-/-) mice explained the late innate production of IFN-γ by the liver in TLR4(-/-) mice in this low dose E. coli peritonitis model. In contrast, early TLR4-induced IFN-γ production is described as a hallmark in high dose E. coli peritonitis models. The present study displays how the kinetics of pro- and anti-inflammatory mechanisms are regulated by TLRs during peritonitis by a gradually growing E. coli load and how these kinetics may affect outcome.
Highlights
Production and release of bactericidal factors and the inflammatory response with recruitment of phagocytes to the site of infection that seek to engulf and kill the microbes
We investigated the contribution of TLR4, TLR2, TIR domain-containing adapter-inducing IFN- (Trif), and myeloid differentiation primary response gene-88 (MyD88) in the initial host defense to E. coli peritonitis instigated by a low intraperitoneal dose of virulent E. coli O18:K1. 6 h after the onset of peritonitis, the bacterial burden was significantly higher in TLR4Ϫ/Ϫ mice compared with WT mice as evaluated in peritoneal lavage fluid (PLF), blood, liver, and lung
TLR2 did not contribute to the initial host response to E. coli peritonitis; bacterial loads were similar in TLR2Ϫ/Ϫ and WT mice in all body compartments examined
Summary
Production and release of bactericidal factors and the inflammatory response with recruitment of phagocytes to the site of infection that seek to engulf and kill the microbes. Despite antibiotic treatment, lethally high dose E. coli (ϳ108 cfu intraperitoneally) model mice can be saved by anti-TLR4 blocking antibodies in conjunction with anti-TLR2 antibodies [17]. We. Role of TLR Signaling during E. coli Peritonitis here delineate the role of the TLR adaptors Trif and MyD88 and the different TLRs in time in a low dose E. coli peritonitis model with a gradually growing bacterial load and dissemination. In contrast to the high dose E. coli intraperitoneal model [17], we here demonstrate that in a low dose E. coli O18:K1 peritonitis model with a gradually growing bacterial load, hepatic IFN-␥ production is enhanced when TLR4 is inactive and that this is associated by absence of SOCS-1 expression. Our results show how low infectious amounts of virulent E. coli up-regulate anti-inflammatory inhibitors through TLR4 and how this may affect the outcome of E. coli peritonitis
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