Interleukin-1 Receptor-Associated Kinase M-Deficient Mice Demonstrate an Improved Host Defense during Gram-negative Pneumonia

Hoogerwerf, Jacobien J.; Windt, Gerritje J. W. van der; Blok, Dana C.; Hoogendijk, Arie J.; Vos, Alex F. de; Veer, Cornelis van ’t; Florquin, Sandrine; Kobayashi, Koichi S.; Flavell, Richard A.; Poll, Tom van der

doi:10.2119/molmed.2011.00450

Cited by 25 publications

(41 citation statements)

References 43 publications

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“…IRAK-M appears to play different roles in other infections and can be either beneficial or deleterious to the host [35], [36], [40], [54], [56]. For example, IRAK-M deficiency led to improved bacterial clearance and host survival in response to both Streptococcus pneumoniae and Klebsiella pneumoniae infections [35], [36].…”

Section: Discussionmentioning

confidence: 99%

IRAK-M Expression Limits Dendritic Cell Activation and Proinflammatory Cytokine Production in Response to Helicobacter pylori

et al. 2013

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Helicobacter pylori (H. pylori) infects the gastric mucosa and persists for the life of the host. Bacterial persistence may be due to the induction of regulatory T cells (Tregs) whichmay have protective effects against other diseases such as asthma. It has been shown that H. pylori modulates the T cell response through dendritic cell reprogramming but the molecular pathways involved are relatively unknown. The goal of this study was to identify critical elements of dendritic cell (DC) activation and evaluate potential influence on immune activation. Microarray analysis was used to demonstrate limited gene expression changes in H. pylori stimulated bone marrow derived DCs (BMDCs) compared to the BMDCs stimulated with E. coli. IRAK-M, a negative regulator of TLR signaling, was upregulated and we selectedit for investigation of its role in modulating the DC and T cell responses. IRAK-M−/− and wild type BMDC were compared for their response to H. pylori. Cells lacking IRAK-M produced significantly greater amounts of proinflammatory MIP-2 and reduced amounts of immunomodulatory IL-10 than wild type BMDC. IRAK-M−/− cells also demonstrated increased MHC II expression upon activation. However, IRAK-M−/− BMDCs were comparable to wild type BMDCs in inducing T-helper 17 (TH17) and Treg responses as demonstrated in vitro using BMDC CD4+ T cells co-culture assays,and in vivo though the adoptive transfer of CD4+ FoxP3-GFP T cells into H. pylori infected IRAK-M−/− mice. These results suggest that H. pylori infection leads to the upregulation of anti-inflammatory molecules like IRAK-M and that IRAK-M has a direct impact on innate functions in DCs such as cytokine and costimulation molecule upregulation but may not affect T cell skewing.

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Section: Discussionmentioning

confidence: 99%

IRAK-M Expression Limits Dendritic Cell Activation and Proinflammatory Cytokine Production in Response to Helicobacter pylori

et al. 2013

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“…Currently, there are no effective therapies to treat this deadly immune disorder. Pneumonia is the most frequent source of sepsis [2]. In that regard, nosocomial infections caused by the opportunistic pathogen KPn account for 5-20% of Gram-negative sepsis cases.…”

Section: Introductionmentioning

confidence: 99%

C-type lectin receptor Clec4d plays a protective role in resolution of Gram-negative pneumonia

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Binstock

Mishra

et al. 2013

Journal of Leukocyte Biology

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Pneumonia is frequently associated with sepsis, characterized by a nonresolving hyperinflammation. However, specific host components of the pulmonary milieu that regulate the perpetuation of inflammation and tissue destruction observed in this immune disorder are not clearly understood. We examined the function of Clec4d, an orphan mammalian CLR, in Gram negative pneumonic sepsis caused by KPn. Whereas the WT mice infected with a sublethal dose of bacteria could resolve the infection, the Clec4d(-/-) mice were highly susceptible with a progressive increase in bacterial burden, hyperinflammatory response typical of sepsis, and severe lung pathology. This correlated with a massive accumulation of neutrophils in lungs of infected Clec4d(-/-) mice, which was in contrast with their WT counterparts, where neutrophils transiently infiltrated the lungs. Interestingly, the Clec4d(-/-) neutrophils did not exhibit any defect in bacterial clearance. These results suggest that Clec4d plays an important role in resolution of inflammation, possibly by facilitating neutrophil turnover in lungs. This is the first report depicting the physiological function of Clec4d in a pathological condition. The results can have implications not only in sepsis but also in other inflammatory diseases, where nonresolving inflammation is the root cause of disease development.

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“…Unlike the limited role of ST2 described here, irak-m −/− mice showed a strongly enhanced detrimental inflammatory response after infection with influenza [60]. In addition, our laboratory recently reported an accelerated innate immune response in irak-m −/− mice upon infection with S. pneumoniae or Klebsiella pneumoniae resulting in a diminished bacterial growth [35], [61]. In contrast, we did not observe an effect of ST2 deficiency on bacterial burdens during primary S. pneumoniae pneumonia (data not shown) and found only a limited effect of ST2 deficiency on bacterial loads during postinfluenza pneumococcal pneumonia.…”

Section: Discussionmentioning

confidence: 64%

Limited Anti-Inflammatory Role for Interleukin-1 Receptor Like 1 (ST2) in the Host Response to Murine Postinfluenza Pneumococcal Pneumonia

et al. 2013

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Interleukin-1 receptor like 1 (ST2) is a negative regulator of Toll-like receptor (TLR) signaling. TLRs are important for host defense during respiratory tract infections by both influenza and Streptococcus (S.) pneumoniae. Enhanced susceptibility to pneumococcal pneumonia is an important complication following influenza virus infection. We here sought to determine the role of ST2 in primary influenza A infection and secondary pneumococcal pneumonia. ST2 knockout (st2 −/−) and wild-type (WT) mice were intranasally infected with influenza A virus; in some experiments mice were infected 2 weeks later with S. pneumoniae. Both mouse strains cleared the virus similarly during the first 14 days of influenza infection and had recovered their weights equally at day 14. Overall st2−/− mice tended to have a stronger pulmonary inflammatory response upon infection with influenza; especially 14 days after infection modest but statistically significant elevations were seen in lung IL-6, IL-1β, KC, IL-10, and IL-33 concentrations and myeloperoxidase levels, indicative of enhanced neutrophil activity. Interestingly, bacterial lung loads were higher in st2−/− mice during the later stages of secondary pneumococcal pneumonia, which was associated with relatively increased lung IFN-γ levels. ST2 deficiency did not impact on gross lung pathology in either influenza or secondary S. pneumoniae pneumonia. These data show that ST2 plays a limited anti-inflammatory role during both primary influenza and postinfluenza pneumococcal pneumonia.

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Interleukin-1 Receptor-Associated Kinase M-Deficient Mice Demonstrate an Improved Host Defense during Gram-negative Pneumonia

Cited by 25 publications

References 43 publications

IRAK-M Expression Limits Dendritic Cell Activation and Proinflammatory Cytokine Production in Response to Helicobacter pylori

IRAK-M Expression Limits Dendritic Cell Activation and Proinflammatory Cytokine Production in Response to Helicobacter pylori

C-type lectin receptor Clec4d plays a protective role in resolution of Gram-negative pneumonia

Limited Anti-Inflammatory Role for Interleukin-1 Receptor Like 1 (ST2) in the Host Response to Murine Postinfluenza Pneumococcal Pneumonia

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