TY - JOUR
T1 - IRF3 signaling within the mouse stroma influences sepsis pathogenesis
AU - Heipertz, Erica L.
AU - Harper, Jourdan
AU - Goswami, Dinesh G.
AU - Lopez, Charlie A.
AU - Nellikappallil, Jose
AU - Zamora, Ruben
AU - Vodovotz, Yoram
AU - Walker, Wendy E.
N1 - Publisher Copyright:
Copyright © 2021 by The American Association of Immunologists, Inc. All rights reserved.
PY - 2021/1/15
Y1 - 2021/1/15
N2 - 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-a, IL-1b, 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.
AB - 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-a, IL-1b, 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.
UR - http://www.scopus.com/inward/record.url?scp=85099427449&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1900217
DO - 10.4049/jimmunol.1900217
M3 - Article
C2 - 33239421
AN - SCOPUS:85099427449
SN - 0022-1767
VL - 206
SP - 398
EP - 409
JO - Journal of Immunology
JF - Journal of Immunology
IS - 2
ER -