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IFN-mediated negative feedback supports bacteria class-specific macrophage inflammatory responses

Despite existing evidence for tuning of innate immunity to different classes of bacteria, the molecular mechanisms used by macrophages to tailor inflammatory responses to specific pathogens remain incompletely defined. By stimulating mouse macrophages with a titration matrix of TLR ligand pairs, we...

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Autores principales: Gottschalk, Rachel A, Dorrington, Michael G, Dutta, Bhaskar, Krauss, Kathleen S, Martins, Andrew J, Uderhardt, Stefan, Chan, Waipan, Tsang, John S, Torabi-Parizi, Parizad, Fraser, Iain DC, Germain, Ronald N
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684266/
https://www.ncbi.nlm.nih.gov/pubmed/31385572
http://dx.doi.org/10.7554/eLife.46836
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author Gottschalk, Rachel A
Dorrington, Michael G
Dutta, Bhaskar
Krauss, Kathleen S
Martins, Andrew J
Uderhardt, Stefan
Chan, Waipan
Tsang, John S
Torabi-Parizi, Parizad
Fraser, Iain DC
Germain, Ronald N
author_facet Gottschalk, Rachel A
Dorrington, Michael G
Dutta, Bhaskar
Krauss, Kathleen S
Martins, Andrew J
Uderhardt, Stefan
Chan, Waipan
Tsang, John S
Torabi-Parizi, Parizad
Fraser, Iain DC
Germain, Ronald N
author_sort Gottschalk, Rachel A
collection PubMed
description Despite existing evidence for tuning of innate immunity to different classes of bacteria, the molecular mechanisms used by macrophages to tailor inflammatory responses to specific pathogens remain incompletely defined. By stimulating mouse macrophages with a titration matrix of TLR ligand pairs, we identified distinct stimulus requirements for activating and inhibitory events that evoked diverse cytokine production dynamics. These regulatory events were linked to patterns of inflammatory responses that distinguished between Gram-positive and Gram-negative bacteria, both in vitro and after in vivo lung infection. Stimulation beyond a TLR4 threshold and Gram-negative bacteria-induced responses were characterized by a rapid type I IFN-dependent decline in inflammatory cytokine production, independent of IL-10, whereas inflammatory responses to Gram-positive species were more sustained due to the absence of this IFN-dependent regulation. Thus, disparate triggering of a cytokine negative feedback loop promotes tuning of macrophage responses in a bacteria class-specific manner and provides context-dependent regulation of inflammation dynamics.
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spelling pubmed-66842662019-08-09 IFN-mediated negative feedback supports bacteria class-specific macrophage inflammatory responses Gottschalk, Rachel A Dorrington, Michael G Dutta, Bhaskar Krauss, Kathleen S Martins, Andrew J Uderhardt, Stefan Chan, Waipan Tsang, John S Torabi-Parizi, Parizad Fraser, Iain DC Germain, Ronald N eLife Computational and Systems Biology Despite existing evidence for tuning of innate immunity to different classes of bacteria, the molecular mechanisms used by macrophages to tailor inflammatory responses to specific pathogens remain incompletely defined. By stimulating mouse macrophages with a titration matrix of TLR ligand pairs, we identified distinct stimulus requirements for activating and inhibitory events that evoked diverse cytokine production dynamics. These regulatory events were linked to patterns of inflammatory responses that distinguished between Gram-positive and Gram-negative bacteria, both in vitro and after in vivo lung infection. Stimulation beyond a TLR4 threshold and Gram-negative bacteria-induced responses were characterized by a rapid type I IFN-dependent decline in inflammatory cytokine production, independent of IL-10, whereas inflammatory responses to Gram-positive species were more sustained due to the absence of this IFN-dependent regulation. Thus, disparate triggering of a cytokine negative feedback loop promotes tuning of macrophage responses in a bacteria class-specific manner and provides context-dependent regulation of inflammation dynamics. eLife Sciences Publications, Ltd 2019-08-06 /pmc/articles/PMC6684266/ /pubmed/31385572 http://dx.doi.org/10.7554/eLife.46836 Text en http://creativecommons.org/publicdomain/zero/1.0/ http://creativecommons.org/publicdomain/zero/1.0/This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication (http://creativecommons.org/publicdomain/zero/1.0/) .
spellingShingle Computational and Systems Biology
Gottschalk, Rachel A
Dorrington, Michael G
Dutta, Bhaskar
Krauss, Kathleen S
Martins, Andrew J
Uderhardt, Stefan
Chan, Waipan
Tsang, John S
Torabi-Parizi, Parizad
Fraser, Iain DC
Germain, Ronald N
IFN-mediated negative feedback supports bacteria class-specific macrophage inflammatory responses
title IFN-mediated negative feedback supports bacteria class-specific macrophage inflammatory responses
title_full IFN-mediated negative feedback supports bacteria class-specific macrophage inflammatory responses
title_fullStr IFN-mediated negative feedback supports bacteria class-specific macrophage inflammatory responses
title_full_unstemmed IFN-mediated negative feedback supports bacteria class-specific macrophage inflammatory responses
title_short IFN-mediated negative feedback supports bacteria class-specific macrophage inflammatory responses
title_sort ifn-mediated negative feedback supports bacteria class-specific macrophage inflammatory responses
topic Computational and Systems Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684266/
https://www.ncbi.nlm.nih.gov/pubmed/31385572
http://dx.doi.org/10.7554/eLife.46836
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