Type I IFN Modulates Host Defense and Late Hyperinflammation in Septic Peritonitis

Abstract

TLRs are considered important for the control of immune responses during endotoxic shock or polymicrobial sepsis. Signaling by TLRs may proceed through the adapter proteins MyD88 or TIR domain-containing adaptor inducinng IFN-β. Both pathways can lead to the production of type I IFNs (IFN-αβ). In the present study, the role of the type I IFN pathway for host defense and immune pathology in sepsis was investigated using a model of mixed bacterial peritonitis. Systemic levels of IFN-αβ protein were markedly elevated during septic peritonitis. More detailed analyses revealed production of IFN-β, but not IFN-α subtypes, and identified CD11b+CD11c− macrophage-like cells as major producers of IFN-β. The results further demonstrate that in IFN-αβ receptor I chain (IFNARI)-deficient mice, the early recruitment of neutrophils to the infected peritoneal cavity was augmented, most likely due to an increased local production of MCP-1 and leukotriene B4. In the absence of IFNARI, peritoneal neutrophils also exhibited enhanced production of reactive oxygen intermediates and elevated expression of Mac-1. Conversely, administration of recombinant IFN-β resulted in reduced leukotriene B4 levels and decreased peritoneal neutrophil recruitment and activation. Analysis of the cytokine response to septic peritonitis revealed that IFNARI deficiency strongly attenuated late, but not early, hyperinflammation. In accordance with these findings, bacterial clearance and overall survival of IFNARI−/− mice were improved. Therefore, the present study reveals critical functions of the type I IFN pathway during severe mixed bacterial infections leading to sepsis. The results suggest that type I IFN exerts predominantly adverse effects under these conditions.

Role for MyD88-Independent, TRIF Pathway in Lipid A/TLR4-Induced Endotoxin Tolerance

“…One of the reasons believed to explain the occurrence of endotoxin-tolerant phenotype in septicemia and systemic inflammatory response syndrome patients (1,5,6) is the high levels of inflammatory cytokines in the circulating serum which desensitize the blood-borne inflammatory cells. Markedly elevated systemic levels of type I IFNs, especially, macrophage-associated IFN-␤, has been noted in cases of septic peritonitis (42). Our observations on up-regulated IFN-␤ production by LPA-homotolerant cells support this fact (Fig.…”

“…This is in line with recent data from IFN-␤ knockout mice which show defective inflammatory cytokine production (e.g., TNF, IL-6, and IL-12p40) and resistance to endotoxin shock (41). Another study using IFNAR1 knockout mice in the septic peritonitis model indicated that IFNAR1 deficiency can strongly attenuate late, but not early, hyperinflammation (42). These evidences collectively suggest the importance of the TRIF/IFN-␤ pathway in mediating the late-phase (sustained) expression of inflammatory cytokines like TNF-␣, as suggested recently (37,54).…”

“…Furthermore, microarray analysis of LPS transcriptome has demonstrated that the majority of LPS-inducible genes are regulated in a MyD88-independent fashion, suggesting a crucial role for the TRIF pathway in inflammatory responses (40). In addition, characterization of IFN-␤-deficient mice has demonstrated their resistance to endotoxin shock and a crucial requirement of IFN-␤ in mediating expression of proinflammatory cytokines at late time points (41,42). These observations make it tempting to speculate that the MyD88-independent TRIF pathway downstream of TLR4 might play a nontrivial role in generating endotoxin tolerance.…”

Bacterial Endotoxin Induces the Release of High Mobility Group Box 1 via the IFN-β Signaling Pathway

“…7B). These data were also surprising, because IFNAR Ϫ/Ϫ mice were reported to be less succumbed to polymicrobial sepsis (42). The reason for this discrepancy is currently not clear.…”

Colon Ascendens Stent Peritonitis (CASP) - a Standardized Model for Polymicrobial Abdominal Sepsis

“…CASP can be applied for all questions around sepsis or peritonitis and is therefore useful for all disciplines dealing with sepsis research, for example immunology, pharmacology, surgery, intensive care medicine, etc. A selection of publications concerning different subjects of sepsis using the CASP model is given below (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14).…”