IRF3 inhibits inflammatory signaling pathways in macrophages to prevent viral pathogenesis

Sukanya Chakravarty; Merina Varghese; Shumin Fan; Roger Travis Taylor; Ritu Chakravarti; Saurabh Chattopadhyay

doi:10.1126/sciadv.adn2858

IRF3 inhibits inflammatory signaling pathways in macrophages to prevent viral pathogenesis

Sukanya Chakravarty, Merina Varghese, Shumin Fan, Roger Travis Taylor, Ritu Chakravarti, Saurabh Chattopadhyay

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8 Scopus citations

Abstract

Viral inflammation contributes to pathogenesis and mortality during respiratory virus infections. IRF3, a critical component of innate antiviral immune responses, interacts with pro-inflammatory transcription factor NF-κB, and inhibits its activity. This mechanism helps suppress inflammatory gene expression in virus-infected cells and mice. We evaluated the cells responsible for IRF3-mediated suppression of viral inflammation using newly engineered conditional Irf3Δ/Δ mice. Irf3Δ/Δ mice, upon respiratory virus infection, showed increased susceptibility and mortality. Irf3 deficiency caused enhanced inflammatory gene expression, lung inflammation, immunopathology, and damage, accompanied by increased infiltration of pro-inflammatory macrophages. Deletion of Irf3 in macrophages (Irf3MKO) displayed, similar to Irf3Δ/Δ mice, increased inflammatory responses, macrophage infiltration, lung damage, and lethality, indicating that IRF3 in these cells suppressed lung inflammation. RNA-seq analyses revealed enhanced NF-κB- dependent gene expression along with activation of inflammatory signaling pathways in infected Irf3MKO lungs. Targeted analyses revealed activated MAPK signaling in Irf3MKO lungs. Therefore, IRF3 inhibited inflammatory signaling pathways in macrophages to prevent viral inflammation and pathogenesis.

Original language	English
Article number	adn2858
Journal	Science advances
Volume	10
Issue number	32
DOIs	https://doi.org/10.1126/sciadv.adn2858
State	Published - Aug 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors.

Funding

We thank G. Sen for providing the Irf3-fl mice, K. Pan, R. Worth, and M. Vijay-Kumar for input on the study and J. Kim and R. Harris for technical assistance. The following reagents were obtained through BEI Resources, National Institute of Allergy and Infectious Diseases, NIH: recombinant murine coronavirus strain icA59 (NR-43000) and mouse macrophage WT cell line (NR-9456). Funding: This work was supported partly by the National Institutes of Health grants AI155545 (to S.Chat.), AI165521 (to S.Chat.), AA027456 (to S.Chat.), AI153496 (to R.T.T.), and AI184880 (to R.C.) and the American Heart Association pre-doctoral fellowship 1019592 (to S.Chak.). Author contributions: S.Chak.:Writing-original draft, conceptualization, investigation, writing-review and editing, methodology, resources, funding acquisition, data curation, validation, supervision, formal analysis, project administration, and visualization. M.V.: Writing-original draft, investigation, writing-review and editing, validation, formal analysis, and visualization. S.F.: Investigation, resources, validation, formal analysis, and visualization. R.T.T.: Conceptualization, methodology, resources, funding acquisition, supervision, and project administration. R.C.: Conceptualization, writing-review and editing, methodology, resources, and supervision. S.Chat.: Writing- original draft, conceptualization, investigation, writing-review and editing, methodology, resources, funding acquisition, data curation, validation, supervision, formal analysis, project administration, and visualization. Competing interests: The authors declare that they have no competing interests. Data and materials availability: The RNA-seq data have been uploaded into GEO (accession number GSE267631). Mice generated in the study may be provided by S.Chat. All other data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Acknowledgments: We thank G. Sen for providing the Irf3-fl mice, K. Pan, R. Worth, and M. vijay-Kumar for input on the study and J. Kim and R. harris for technical assistance. the following reagents were obtained through Bei Resources, national institute of Allergy and infectious diseases, nih: recombinant murine coronavirus strain icA59 (nR-43000) and mouse macrophage Wt cell line (nR-9456). Funding: this work was supported partly by the national institutes of health grants Ai155545 (to S.Chat.), Ai165521 (to S.Chat.), AA027456 (to S.Chat.), Ai153496 (to R.t.t.), and Ai184880 (to R.C.) and the American heart Association pre-doctoral fellowship 1019592 (to S.Chak.). Author contributions: S.Chak.:Writing—original draft, conceptualization, investigation, writing—review and editing, methodology, resources, funding acquisition, data curation, validation, supervision, formal analysis, project administration, and visualization. M.v.: Writing—original draft, investigation, writing—review and editing, validation, formal analysis, and visualization. S.F.: investigation, resources, validation, formal analysis, and visualization. R.t.t.: Conceptualization, methodology, resources, funding acquisition, supervision, and project administration. R.C.: Conceptualization, writing—review and editing, methodology, resources, and supervision. S.Chat.: Writing— original draft, conceptualization, investigation, writing—review and editing, methodology, resources, funding acquisition, data curation, validation, supervision, formal analysis, project administration, and visualization. Competing interests: the authors declare that they have no competing interests. Data and materials availability: the RnA-seq data have been uploaded into GeO (accession number GSe267631). Mice generated in the study may be provided by S.Chat. All other data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.

Funders	Funder number
National Institute of Allergy and Infectious F32-AI286447 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R01AI168214 Jason W. Rosch Diseases National Institute of Allergy and Infectious P30 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R00-AI166116 Christopher D. Radka Diseases National Institute of Allergy and Infectious T32-AI106700 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R01AI192221 Jason W. Rosch Diseases National Inst...
BEI Resources
National Institutes of Health (NIH)	NR-43000, AA027456, AI184880, AI155545, AI153496, NR-9456, AI165521
American the American Heart Association	1019592, GSE267631

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title = "IRF3 inhibits inflammatory signaling pathways in macrophages to prevent viral pathogenesis",

abstract = "Viral inflammation contributes to pathogenesis and mortality during respiratory virus infections. IRF3, a critical component of innate antiviral immune responses, interacts with pro-inflammatory transcription factor NF-κB, and inhibits its activity. This mechanism helps suppress inflammatory gene expression in virus-infected cells and mice. We evaluated the cells responsible for IRF3-mediated suppression of viral inflammation using newly engineered conditional Irf3Δ/Δ mice. Irf3Δ/Δ mice, upon respiratory virus infection, showed increased susceptibility and mortality. Irf3 deficiency caused enhanced inflammatory gene expression, lung inflammation, immunopathology, and damage, accompanied by increased infiltration of pro-inflammatory macrophages. Deletion of Irf3 in macrophages (Irf3MKO) displayed, similar to Irf3Δ/Δ mice, increased inflammatory responses, macrophage infiltration, lung damage, and lethality, indicating that IRF3 in these cells suppressed lung inflammation. RNA-seq analyses revealed enhanced NF-κB- dependent gene expression along with activation of inflammatory signaling pathways in infected Irf3MKO lungs. Targeted analyses revealed activated MAPK signaling in Irf3MKO lungs. Therefore, IRF3 inhibited inflammatory signaling pathways in macrophages to prevent viral inflammation and pathogenesis.",

author = "Sukanya Chakravarty and Merina Varghese and Shumin Fan and Taylor, \{Roger Travis\} and Ritu Chakravarti and Saurabh Chattopadhyay",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors.",

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doi = "10.1126/sciadv.adn2858",

language = "English",

volume = "10",

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AU - Chakravarty, Sukanya

AU - Varghese, Merina

AU - Fan, Shumin

AU - Taylor, Roger Travis

AU - Chakravarti, Ritu

AU - Chattopadhyay, Saurabh

PY - 2024/8

Y1 - 2024/8

N2 - Viral inflammation contributes to pathogenesis and mortality during respiratory virus infections. IRF3, a critical component of innate antiviral immune responses, interacts with pro-inflammatory transcription factor NF-κB, and inhibits its activity. This mechanism helps suppress inflammatory gene expression in virus-infected cells and mice. We evaluated the cells responsible for IRF3-mediated suppression of viral inflammation using newly engineered conditional Irf3Δ/Δ mice. Irf3Δ/Δ mice, upon respiratory virus infection, showed increased susceptibility and mortality. Irf3 deficiency caused enhanced inflammatory gene expression, lung inflammation, immunopathology, and damage, accompanied by increased infiltration of pro-inflammatory macrophages. Deletion of Irf3 in macrophages (Irf3MKO) displayed, similar to Irf3Δ/Δ mice, increased inflammatory responses, macrophage infiltration, lung damage, and lethality, indicating that IRF3 in these cells suppressed lung inflammation. RNA-seq analyses revealed enhanced NF-κB- dependent gene expression along with activation of inflammatory signaling pathways in infected Irf3MKO lungs. Targeted analyses revealed activated MAPK signaling in Irf3MKO lungs. Therefore, IRF3 inhibited inflammatory signaling pathways in macrophages to prevent viral inflammation and pathogenesis.

AB - Viral inflammation contributes to pathogenesis and mortality during respiratory virus infections. IRF3, a critical component of innate antiviral immune responses, interacts with pro-inflammatory transcription factor NF-κB, and inhibits its activity. This mechanism helps suppress inflammatory gene expression in virus-infected cells and mice. We evaluated the cells responsible for IRF3-mediated suppression of viral inflammation using newly engineered conditional Irf3Δ/Δ mice. Irf3Δ/Δ mice, upon respiratory virus infection, showed increased susceptibility and mortality. Irf3 deficiency caused enhanced inflammatory gene expression, lung inflammation, immunopathology, and damage, accompanied by increased infiltration of pro-inflammatory macrophages. Deletion of Irf3 in macrophages (Irf3MKO) displayed, similar to Irf3Δ/Δ mice, increased inflammatory responses, macrophage infiltration, lung damage, and lethality, indicating that IRF3 in these cells suppressed lung inflammation. RNA-seq analyses revealed enhanced NF-κB- dependent gene expression along with activation of inflammatory signaling pathways in infected Irf3MKO lungs. Targeted analyses revealed activated MAPK signaling in Irf3MKO lungs. Therefore, IRF3 inhibited inflammatory signaling pathways in macrophages to prevent viral inflammation and pathogenesis.

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IRF3 inhibits inflammatory signaling pathways in macrophages to prevent viral pathogenesis

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