Author:
Bomfim Caio C. B.,Fisher Logan,Amaral Eduardo P.,Mittereder Lara,McCann Katelyn,Correa André A. S.,Namasivayam Sivaranjani,Swamydas Muthulekha,Moayeri Mahtab,Weiss Jonathan M.,Chari Raj,McVicar Daniel W.,Costa Diego L.,D’Império Lima Maria R.,Sher Alan
Abstract
Irg1 is an enzyme that generates itaconate, a metabolite that plays a key role in the regulation of inflammatory responses. Previous studies have implicated Irg1 as an important mediator in preventing excessive inflammation and tissue damage inMycobacterium tuberculosis(Mtb) infection. Here, we investigated the pattern recognition receptors and signaling pathways by whichMtbtriggers Irg1 gene expression by comparing the responses of control and genetically deficient BMDMs. Using this approach, we demonstrated partial roles for TLR-2 (but not TLR-4 or -9), MyD88 and NFκB signaling in Irg1 induction byMtbbacilli. In addition, drug inhibition studies revealed major requirements for phagocytosis and endosomal acidification in Irg1 expression triggered byMtbbut not LPS or PAM3CSK4. Importantly, theMtb-induced Irg1 response was highly dependent on the presence of the bacterial ESX-1 secretion system, as well as host STING and Type I IFN receptor (IFNAR) signaling with Type II IFN (IFN-γ) signaling playing only a minimal role. Based on these findings we hypothesize thatMtbinduces Irg1 expression in macrophagesviathe combination of two independent triggers both dependent on bacterial phagocytosis: 1) a major signal stimulated by phagocytizedMtbproducts released by an ESX-1-dependent mechanism into the cytosol where they activate the STING pathway leading to Type I-IFN production, and 2) a secondary TLR-2, MyD88 and NFκB dependent signal that enhances Irg1 production independently of Type I IFN induction.
Funder
Division of Intramural Research, National Institute of Allergy and Infectious Diseases
Division of Cancer Prevention, National Cancer Institute
Fundação de Amparo à Pesquisa do Estado de São Paulo
Subject
Infectious Diseases,Microbiology (medical),Immunology,Microbiology
Cited by
28 articles.
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