Interleukin 1 Receptor–Associated Kinase M Impairs Host Defense During Pneumococcal Pneumonia

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

doi:10.1093/infdis/jis290

Cited by 26 publications

(50 citation statements)

References 45 publications

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“…Similarly, the importance of single immunoglobulin IL-1 receptor-related molecule (SIGIRR), a transmembrane molecule that inhibits TLR signaling, in attenuating the antibacterial response was observed in pneumococcal pneumonia (63), whereas its deficiency proved beneficial for survival and bacterial clearance during P. aeruginosa-induced pneumonia (64), indicating the nonredundant but specific role of this negative regulator in lower respiratory tract infection. Additionally, S. pneumoniae and Klebsiella both exploit host IRAK-M, a regulator that inhibits the activity of IRAKs, to evade pulmonary immune responses (65,66). Additionally, it has recently been shown that M. tuberculosis suppresses Th1 activation via DAP12-mediated induction of IRAK-M, which in turn induces IL-10 expression by antigen-presenting cells (67).…”

Section: Methods Used By Pathogenic Pulmonary Bacteria To Circumvent mentioning

confidence: 99%

Divergent Functions of Toll-like Receptors during Bacterial Lung Infections

Baral

Batra

Zemans

et al. 2014

Am J Respir Crit Care Med

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Lower respiratory tract infections caused by bacteria are a major cause of death in humans irrespective of sex, race, or geography. Indeed, accumulated data indicate greater mortality and morbidity due to these infections than cancer, malaria, or HIV infection. Successful recognition of, followed by an appropriate response to, bacterial pathogens in the lungs is crucial for effective pulmonary host defense. Although the early recruitment and activation of neutrophils in the lungs is key in the response against invading microbial pathogens, other sentinels, such as alveolar macrophages, epithelial cells, dendritic cells, and CD41 T cells, also contribute to the elimination of the bacterial burden. Pattern recognition receptors, such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptors, are important for recognizing and responding to microbes during pulmonary infections. However, bacterial pathogens have acquired crafty evasive strategies to circumvent the pattern recognition receptor response and thus establish infection. Increased understanding of the function of TLRs and evasive mechanisms used by pathogens during pulmonary infection will deepen our knowledge of immunopathogenesis and is crucial for developing effective therapeutic and/or prophylactic measures. This review summarizes current knowledge of the multiple roles of TLRs in bacterial lung infections and highlights the mechanisms used by pathogens to modulate or interfere with TLR signaling in the lungs.

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Section: Methods Used By Pathogenic Pulmonary Bacteria To Circumvent mentioning

confidence: 99%

Divergent Functions of Toll-like Receptors during Bacterial Lung Infections

Baral

Batra

Zemans

et al. 2014

Am J Respir Crit Care Med

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“…The models of pneumococcal pneumonia and pneumococcal sepsis have previously been described [23,24]. In short, mice were inoculated intranasally (to induce pneumonia) with 5 × 10 4 CFU of S. pneumoniae (serotype 3; American Type Culture Collection, ATCC 6303, Rockville, Md., USA) or intravenously (to induce primary sepsis) with 5 × 10 5 CFU S. pneumoniae.…”

Section: Methodsmentioning

confidence: 99%

“…In short, mice were inoculated intranasally (to induce pneumonia) with 5 × 10 4 CFU of S. pneumoniae (serotype 3; American Type Culture Collection, ATCC 6303, Rockville, Md., USA) or intravenously (to induce primary sepsis) with 5 × 10 5 CFU S. pneumoniae. Lungs, blood, spleens, and livers were harvested 6, 24, or 48 h postinfection for quantitative bacterial cultures as described (n = 8 or 16 per group at each time point) [23,24]. Neutrophil counts in bronchoalveolar lavage (BAL) fluid were determined as described [25].…”

Section: Methodsmentioning

confidence: 99%

Single Immunoglobulin Interleukin-1 Receptor-Related Molecule Impairs Host Defense during Pneumonia and Sepsis Caused by <b><i>Streptococcus Pneumoniae</i></b>

et al. 2014

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Streptococcus pneumoniae is a common cause of pneumonia and sepsis. Toll-like receptors (TLRs) play a pivotal role in the host defense against infection. In this study, we sought to determine the role of single immunoglobulin interleukin-1 receptor-related molecule (SIGIRR a.k.a. TIR8), a negative regulator of TLR signaling, in pneumococcal pneumonia and sepsis. Wild-type and SIGIRR-deficient (sigirr-/-) mice were infected intranasally (to induce pneumonia) or intravenously (to induce primary sepsis) with S. pneumoniae and euthanized after 6, 24, or 48 h for analyses. Additionally, survival studies were performed. sigirr-/- mice showed delayed mortality during lethal pneumococcal pneumonia. Accordingly, sigirr-/- mice displayed lower bacterial loads in lungs and less dissemination of the infection 24 h after the induction of pneumonia. SIGIRR deficiency was associated with increased interstitial and perivascular inflammation in lung tissue early after infection, with no impact on neutrophil recruitment or cytokine production. sigirr-/- mice also demonstrated reduced bacterial burdens at multiple body sites during S. pneumoniae sepsis. sigirr-/- alveolar macrophages and neutrophils exhibited an increased capacity to phagocytose viable pneumococci. These results suggest that SIGIRR impairs the antibacterial host defense during pneumonia and sepsis caused by S. pneumoniae.

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“…IRAK-M is expressed in monocytes/macrophages and in lung epithelial cells and IRAK-M is an important factor to down-regulate host defense in bacterial pneumonia models [1,[14][15][16]19]. In order to study the potential proand anti-inflammatory effects of human WT IRAK-M and the DD mutants on TLR mediated cytokine/chemokine release we stably introduced these proteins in human monocytic cells (THP-1) and in human bronchial lung epithelial cells (H292).…”

Section: Potency Of Irak-m-dd Mutants To Inhibit Tlr Signaling In Macmentioning

confidence: 99%

“…Furthermore, IRAK-M was shown to inhibit the IRAK-2 dependent mRNA stabilization/translation of cytokines and chemokines [13]. Increased host responses caused by lack of IRAK-M are favorable for the clinical outcome in bacterial pneumonia [14][15][16], but also in tumor models [17] and bone marrow transplantation [18] which implies that inhibition of IRAK-M might have therapeutic potential. Different from the other IRAK's, IRAK-M expression is rather restricted to certain cell types such as monocytes/macrophages and lung epithelial cells [1,19] and IRAK-M is up-regulated under inflammatory conditions and associated with LPS tolerance [9,20].…”

Section: Introductionmentioning

confidence: 99%

The structure function of the death domain of human IRAK-M

Nicolaes

Kruijswijk

et al. 2014

Cell Communication and Signaling

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Background: IRAK-M is an inhibitor of Toll-like receptor signaling that acts by re-directing IRAK-4 activity to TAK1 independent NF-κB activation and by inhibition of IRAK-1/IRAK-2 activity. IRAK-M is expressed in monocytes/macrophages and lung epithelial cells. Lack of IRAK-M in mice greatly improves the resistance to nosocomial pneumonia and lung tumors, which entices IRAK-M as a potential therapeutic target. IRAK-M consists of an N-terminal death domain (DD), a dysfunctional kinase domain and unstructured C-terminal domain. Little is known however on IRAK-M's structure-function relationships.

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Interleukin 1 Receptor–Associated Kinase M Impairs Host Defense During Pneumococcal Pneumonia

Cited by 26 publications

References 45 publications

Divergent Functions of Toll-like Receptors during Bacterial Lung Infections

Divergent Functions of Toll-like Receptors during Bacterial Lung Infections

Single Immunoglobulin Interleukin-1 Receptor-Related Molecule Impairs Host Defense during Pneumonia and Sepsis Caused by <b><i>Streptococcus Pneumoniae</i></b>

The structure function of the death domain of human IRAK-M

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