Back to Search Start Over

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

Authors :
John S. Tsang
Bhaskar Dutta
Andrew J. Martins
Parizad Torabi-Parizi
Waipan Chan
Kathleen S Krauss
Iain D. C. Fraser
Rachel A. Gottschalk
Ronald N. Germain
Stefan Uderhardt
Michael G. Dorrington
Source :
eLife, Vol 8 (2019), eLife
Publication Year :
2019
Publisher :
eLife Sciences Publications, Ltd, 2019.

Abstract

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.

Details

ISSN :
2050084X
Volume :
8
Database :
OpenAIRE
Journal :
eLife
Accession number :
edsair.doi.dedup.....7f6bd5523e0673a759382984c5d0754f
Full Text :
https://doi.org/10.7554/elife.46836