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IRAK1-Dependent Signaling Mediates Mortality in Polymicrobial Sepsis

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Abstract

Interleukin-1 receptor-associated kinase (IRAK1) is a key regulatory protein in TLR/IL1R-mediated cell activation during inflammatory response. Studies indicated that pending on the nature of the used inflammatory model, downregulation of IRAK1 may be beneficial or detrimental. However, the role of IRAK1 in affecting outcome in polymicrobial sepsis is unknown. We tested this question using an IRAK1-deficient mouse strain and cecal ligation and puncture (CLP) procedure, which is a clinically relevant rodent septic model. Sepsis-induced mortality was markedly lower in IRAK1-deficient mice (35 %) compared to WT (85 %). Sepsis-induced increases in blood IL-6 and IL-10 levels were blunted at 6 h post-CLP in IRAK1 deficiency compared to WT, but cytokine levels were similar at 20 h post-CLP. Sepsis-induced blood granulocytosis and depletion of splenic B cells were also blunted in IRAK1-deficient mice as compared to WT. Analysis of TLR-mediated cytokine responses by IRAK1-deficient and WT macrophages ex vivo indicated a TLR4-dependent downregulation of IL-6 and IL1β in IRAK1 deficiency, whereas TLR2-dependent responses were unaffected. TLR7/8-mediated IL-6, IL1β, and IL-10 production was also blunted in IRAK1 macrophages as compared to WT. The study shows that IRAK1 deficiency impacts multiple TLR-dependent pathways and decreases early cytokine responses following polymicrobial sepsis. The delayed inflammatory response caused by the lack of IRAK1 expression is beneficial, as it manifests a marked increased chance of survival after polymicrobial sepsis.

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Abbreviations

PMN:

Polymorphonuclear neutrophils

BM:

Bone marrow

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Acknowledgments

This study was supported by NIH-NIGMS grant GM084932.

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Authors and Affiliations

  1. Department of Surgery, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Ave., MSB G-578, Newark, NJ, 07103, USA

    Rachna Chandra, Stephanie Federici, Tripti Bishwas, Zoltán H. Németh, Edwin A. Deitch & Zoltán Spolarics

  2. Department of Surgery, Morristown Medical Center, Morristown, NJ, USA

    Zoltán H. Németh

  3. Departments of Pediatrics and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    James A. Thomas

Authors
  1. Rachna Chandra
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  2. Stephanie Federici
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  4. Zoltán H. Németh
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  5. Edwin A. Deitch
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  7. Zoltán Spolarics
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Correspondence to Zoltán Spolarics.

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Chandra, R., Federici, S., Bishwas, T. et al. IRAK1-Dependent Signaling Mediates Mortality in Polymicrobial Sepsis. Inflammation 36, 1503–1512 (2013). https://doi.org/10.1007/s10753-013-9692-1

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