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IRF3 Signaling within the Mouse Stroma Influences Sepsis Pathogenesis

Erica L. Heipertz, Jourdan Harper, Dinesh G. Goswami, Charlie A. Lopez, Jose Nellikappallil, Ruben Zamora, Yoram Vodovotz and Wendy E. Walker
J Immunol January 15, 2021, 206 (2) 398-409; DOI: https://doi.org/10.4049/jimmunol.1900217
Erica L. Heipertz
*Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905;
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Jourdan Harper
*Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905;
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Dinesh G. Goswami
*Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905;
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Charlie A. Lopez
*Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905;
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Jose Nellikappallil
†Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905; and
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Ruben Zamora
‡Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213
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Yoram Vodovotz
‡Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213
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Wendy E. Walker
*Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905;
†Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905; and
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Key Points

  • IRF3 contributes to sepsis in a mouse model incorporating antibiotics and fluids.

  • IRF3 acts in stromal cells (nonleukocytes) to mediate this effect.

  • IRF3 indirectly alters macrophage behavior and the inflammatory network in sepsis.

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Abstract

IFN regulatory factor 3 (IRF3) is a transcription factor that is activated by multiple pattern-recognition receptors. We demonstrated previously that IRF3 plays a detrimental role in a severe mouse model of sepsis, induced by cecal ligation and puncture. In this study, we found that IRF3–knockout (KO) mice were greatly protected from sepsis in a clinically relevant version of the cecal ligation and puncture model incorporating crystalloid fluids and antibiotics, exhibiting improved survival, reduced disease score, lower levels of serum cytokines, and improved phagocytic function relative to wild-type (WT) mice. Computational modeling revealed that the overall complexity of the systemic inflammatory/immune network was similar in IRF3-KO versus WT septic mice, although the tempo of connectivity differed. Furthermore, the mediators driving the network differed: TNF-α, IL-1β, and IL-6 predominated in WT mice, whereas MCP-1 and IL-6 predominated in IRF3-KO mice. Network analysis also suggested differential IL-6–related inflammatory programs in WT versus IRF3-KO mice. We created bone marrow chimeras to test the role of IRF3 within leukocytes versus stroma. Surprisingly, chimeras with IRF3-KO bone marrow showed little protection from sepsis, whereas chimeras with IRF3-KO stroma showed a substantial degree of protection. We found that WT and IRF3-KO macrophages had a similar capacity to produce IL-6 and phagocytose bacteria in vitro. Adoptive transfer experiments demonstrated that the genotype of the host environment affected the capacity of monocytes to produce IL-6 during sepsis. Thus, IRF3 acts principally within the stromal compartment to exacerbate sepsis pathogenesis via differential impacts on IL-6–related inflammatory programs.

This article is featured in Top Reads, p.243

Footnotes

  • This work was supported by Texas Tech University Health Sciences Center El Paso startup funds (to W.E.W.), the Shock Society Research Fellowship for Early Career Investigators (to W.E.W.), and National Institutes of Health/National Institute of General Medical Sciences Grant RO1-GM107231-01A1 (to R.Z. and Y.V.).

  • Abbreviations used in this article:

    CLP
    cecal ligation and puncture
    DAMP
    damage-associated molecular pattern
    DyNA
    dynamic network analysis
    21G
    21-gauge
    IRF3
    IFN regulatory factor 3
    KC
    keratinocyte-derived cytokine
    KO
    knockout
    LRS
    lactated Ringer solution
    STING
    stimulator of IFN genes
    TRIF
    TIR domain–containing adapter-inducing IFN-β
    VEGF
    vascular endothelial growth factor
    WT
    wild-type.

  • Received February 21, 2019.
  • Accepted October 20, 2020.
  • Copyright © 2021 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 206 (2)
The Journal of Immunology
Vol. 206, Issue 2
15 Jan 2021
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IRF3 Signaling within the Mouse Stroma Influences Sepsis Pathogenesis
Erica L. Heipertz, Jourdan Harper, Dinesh G. Goswami, Charlie A. Lopez, Jose Nellikappallil, Ruben Zamora, Yoram Vodovotz, Wendy E. Walker
The Journal of Immunology January 15, 2021, 206 (2) 398-409; DOI: 10.4049/jimmunol.1900217

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IRF3 Signaling within the Mouse Stroma Influences Sepsis Pathogenesis
Erica L. Heipertz, Jourdan Harper, Dinesh G. Goswami, Charlie A. Lopez, Jose Nellikappallil, Ruben Zamora, Yoram Vodovotz, Wendy E. Walker
The Journal of Immunology January 15, 2021, 206 (2) 398-409; DOI: 10.4049/jimmunol.1900217
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