Improved host defense against septic peritonitis in mice lacking MyD88 and TRIF is linked to a normal interferon response

Reim, Daniel; Rossmann-Bloeck, Tanja; Jusek, Gabriela; Costa, Olivia Prazeres da; Holzmann, Bernhard

doi:10.1189/jlb.1110602

Cited by 15 publications

(32 citation statements)

References 55 publications

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“…We have shown here that classical NOD ligands have limited capacity to induce miR-155 in macrophages; however, the T4SS-dependent miR-155 up-regulation during infection was independent of NOD1/2 receptor activity, as demonstrated by the use here of MyD88/Trif/Rip2 −/− BMMs. The MyD88/Trif-independent up-regulation of miR-155 observed here displays a phenotype similar to that seen with the induction of TNF-α and type I IFNs or IFN-induced genes, such as CXCL10, demonstrated for intestinal bacteria-infected BMMs (60,61). IFN-β and TNF-α incubation induced miR-155 expression; however, induction of miR-155 by TLR ligands still occurred in the absence of TNF receptors and IFN-α receptors in BMMs (39).…”

Section: Discussionmentioning

confidence: 51%

Induction of microRNA-155 is TLR- and type IV secretion system-dependent in macrophages and inhibits DNA-damage induced apoptosis

Koch

Mollenkopf

Klemm

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

104

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Helicobacter pylori is a gastric pathogen responsible for a high disease burden worldwide. Deregulated inflammatory responses, possibly involving macrophages, are implicated in H. pylori-induced pathology, and microRNAs, such as miR-155, have recently emerged as crucial regulators of innate immunity and inflammatory responses. miR-155 is regulated by Toll-like receptor (TLR) ligands in monocyte-derived cells and has been shown to be induced in macrophages during H. pylori infection. Here, we investigated the regulation of miR-155 expression in primary murine bone marrow-derived macrophages (BMMs) during H. pylori infection and examined the downstream mRNA targets of this micro-RNA using microarray analysis. We report TLR2/4-and NOD1/2-independent up-regulation of miR-155, which was found to be dependent on the major H. pylori pathogenicity determinant, the type IV secretion system (T4SS). miR-155 expression was dependent on NF-κB signaling but was independent of CagA. Microarray analysis identified known gene targets of miR-155 in BMMs during H. pylori infection that are proapoptotic. We also identified and validated miR-155 binding sites in the 3′ UTRs of the targets, Tspan14, Lpin1, and Pmaip1. We observed that H. pylori-infected miR-155 −/− BMMs were significantly more susceptible to cisplatin DNA damage-induced apoptosis than were wild-type BMMs. Thus, our data suggest a function for the prototypical H. pylori pathogenicity factor, the T4SS, in the up-regulation of miR-155 in BMMs. We propose the antiapoptotic effects of miR-155 could enhance macrophage resistance to apoptosis induced by DNA damage during H. pylori infection.pathogen-associated molecular pattern | mucosal immunity

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Section: Discussionmentioning

confidence: 51%

Induction of microRNA-155 is TLR- and type IV secretion system-dependent in macrophages and inhibits DNA-damage induced apoptosis

Koch

Mollenkopf

Klemm

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

104

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“…We have previously demonstrated that TLR2, TLR4 and TLR9 play a deleterious role in polymicrobial sepsis [6]–[8]. However, the beneficial or deleterious role of the adaptor protein MyD88, recruited by these TLRs, to the outcome of polymicrobial sepsis still remains controversial [9]–[13].…”

Section: Introductionmentioning

confidence: 99%

MyD88-, but Not Nod1- and/or Nod2-Deficient Mice, Show Increased Susceptibility to Polymicrobial Sepsis due to Impaired Local Inflammatory Response

et al. 2014

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Pathogen recognition and triggering of the inflammatory response following infection in mammals depend mainly on Toll-like and Nod-like receptors. Here, we evaluated the role of Nod1, Nod2 and MyD88-dependent signaling in the chemokine production and neutrophil recruitment to the infectious site during sepsis induced by cecal ligation and puncture (CLP) in C57Bl/6 mice. We demonstrate that Nod1 and Nod2 are not involved in the release of chemokines and recruitment of neutrophils to the infectious site during CLP-induced septic peritonitis because these events were similar in wild-type, Nod1-, Nod2-, Nod1/Nod2- and Rip2-deficient mice. Consequently, the local and systemic bacterial loads were not altered. Accordingly, neither Nod1 nor Nod2 was involved in the production of the circulating cytokines and in the accumulation of leukocytes in the lungs. By contrast, we showed that MyD88-dependent signaling is crucial for the establishment of the local inflammatory response during CLP-induced sepsis. MyD88-deficient mice were susceptible to sepsis because of an impaired local production of chemokines and defective neutrophil recruitment to the infection site. Altogether, these data show that Nod1, Nod2 and Rip2 are not required for local chemokine production and neutrophil recruitment during CLP-induced sepsis, and they reinforce the importance of MyD88-dependent signaling for initiation of a protective host response.

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“…It is generally thought that very high concentrations of cytokines in the blood late in the course of sepsis contribute to septic shock and are associated with a poor outcome. However, early production of key cytokines can enhance clearance of bacteria and survival in animal models [19,21]. The present study indicated that SMD decreased production of several pro-inflammatory cytokines and chemokines and increased production of IL-10 early in the course of sepsis.…”

Section: Discussionmentioning

confidence: 54%

Effects of sodium methyldithiocarbamate on selected parameters of innate immunity and clearance of bacteria in a mouse model of sepsis

Wang

Pruett

2015

Life Sciences

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Aims Sodium methyldithiocarbamate (SMD), the third most widely used conventional pesticide in the United States, has been reported to inhibit several parameters associated with inflammation and to decrease resistance to infection. In a previous study, survival time was markedly decreased when mice were treated orally with SMD shortly before challenge with a high dose of Escherichia coli (E. coli) that was lethal to most of the control mice. In the present study, we evaluated selected parameters of the innate immune system using a lower challenge dose of E. coli, to determine which (if any) of these parameters reflected continued changes through 24 h. Main methods Bacterial clearance from the peritoneal cavity, production of chemokines and cytokines, and body temperature were measured. Key findings All these parameters were reduced by SMD up to 12 h after bacterial challenge, but the concentration of the anti-inflammatory cytokine IL-10 was increased. Even so, mice in the control and SMD-treated groups cleared most bacteria by 24 h. Other parameters (cytokine concentrations and body temperature) were also normal or near normal by 24 h. The same dosage of SMD administered intranasally also did not significantly decrease survival. Hypothermia from 16 to 28 h correlated with lethal outcome, but SMD significantly increased hypothermia only at 2 and 4 h after challenge. Significance In spite of substantial early inhibition by SMD of parameters known to be important for resistance to infection, bacterial clearance and survival were not altered, suggesting immunological reserve and/or rapid recovery after transient effects of SMD.

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Improved host defense against septic peritonitis in mice lacking MyD88 and TRIF is linked to a normal interferon response

Cited by 15 publications

References 55 publications

Induction of microRNA-155 is TLR- and type IV secretion system-dependent in macrophages and inhibits DNA-damage induced apoptosis

Induction of microRNA-155 is TLR- and type IV secretion system-dependent in macrophages and inhibits DNA-damage induced apoptosis

MyD88-, but Not Nod1- and/or Nod2-Deficient Mice, Show Increased Susceptibility to Polymicrobial Sepsis due to Impaired Local Inflammatory Response

Effects of sodium methyldithiocarbamate on selected parameters of innate immunity and clearance of bacteria in a mouse model of sepsis

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