Inflammation

, Volume 36, Issue 6, pp 1503–1512 | Cite as

IRAK1-Dependent Signaling Mediates Mortality in Polymicrobial Sepsis

  • Rachna Chandra
  • Stephanie Federici
  • Tripti Bishwas
  • Zoltán H. Németh
  • Edwin A. Deitch
  • James A. Thomas
  • Zoltán Spolarics
Article
First Online:

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.

KEY WORDS

infection TLR signaling macrophages survival interleukin 

ABBREVIATIONS

PMN

Polymorphonuclear neutrophils

BM

Bone marrow

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Notes

Acknowledgments

This study was supported by NIH-NIGMS grant GM084932.

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Rachna Chandra
    • 1
  • Stephanie Federici
    • 1
  • Tripti Bishwas
    • 1
  • Zoltán H. Németh
    • 1
    • 2
  • Edwin A. Deitch
    • 1
  • James A. Thomas
    • 3
  • Zoltán Spolarics
    • 1
  1. 1.Department of Surgery, New Jersey Medical SchoolUniversity of Medicine and Dentistry of New JerseyNewarkUSA
  2. 2.Department of SurgeryMorristown Medical CenterMorristownUSA
  3. 3.Departments of Pediatrics and Molecular BiologyUniversity of Texas Southwestern Medical CenterDallasUSA

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