TY - JOUR
T1 - Sterile lung inflammation induced by silica exacerbates mycobacterium tuberculosis infection via STING-dependent type 2 immunity
AU - Benmerzoug, Sulayman
AU - Bounab, Badreddine
AU - Rose, Stéphanie
AU - Gosset, David
AU - Biet, Franck
AU - Cochard, Thierry
AU - Xavier, Aurore
AU - Rouxel, Nathalie
AU - Fauconnier, Louis
AU - Horsnell, William G C
AU - Ryffel, Bernhard
AU - Togbe, Dieudonnee
AU - Quesniaux, Valerie F J
PY - 2019/5/28
Y1 - 2019/5/28
N2 - Lung inflammation induced by silica impairs host control of tuberculosis, yet the underlying mechanism remains unclear. Here, we show that silica-driven exacerbation of M. tuberculosis infection associates with raised type 2 immunity. Silica increases pulmonary Th2 cell and M2 macrophage responses, while reducing type 1 immunity after M. tuberculosis infection. Silica induces lung damage that prompts extracellular self-DNA release and activates STING. This STING priming potentiates M. tuberculosis DNA sensing by and activation of cGAS/STING, which triggers enhanced type I interferon (IFNI) response and type 2 immunity. cGAS-, STING-, and IFNAR-deficient mice are resistant to silica-induced exacerbation of M. tuberculosis infection. Thus, silica-induced self-DNA primes the host response to M. tuberculosis-derived nucleic acids, which increases type 2 immunity while reducing type 1 immunity, crucial for controlling M. tuberculosis infection. These data show how cGAS/STING pathway activation, at the crossroads of sterile inflammation and infection, may affect the host response to pathogens such as M. tuberculosis.
AB - Lung inflammation induced by silica impairs host control of tuberculosis, yet the underlying mechanism remains unclear. Here, we show that silica-driven exacerbation of M. tuberculosis infection associates with raised type 2 immunity. Silica increases pulmonary Th2 cell and M2 macrophage responses, while reducing type 1 immunity after M. tuberculosis infection. Silica induces lung damage that prompts extracellular self-DNA release and activates STING. This STING priming potentiates M. tuberculosis DNA sensing by and activation of cGAS/STING, which triggers enhanced type I interferon (IFNI) response and type 2 immunity. cGAS-, STING-, and IFNAR-deficient mice are resistant to silica-induced exacerbation of M. tuberculosis infection. Thus, silica-induced self-DNA primes the host response to M. tuberculosis-derived nucleic acids, which increases type 2 immunity while reducing type 1 immunity, crucial for controlling M. tuberculosis infection. These data show how cGAS/STING pathway activation, at the crossroads of sterile inflammation and infection, may affect the host response to pathogens such as M. tuberculosis.
UR - http://www.scopus.com/inward/record.url?scp=85065907413&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2019.04.110
DO - 10.1016/j.celrep.2019.04.110
M3 - Article
C2 - 31141689
SN - 2211-1247
VL - 27
SP - 2649-2664.e5
JO - Cell Reports
JF - Cell Reports
IS - 9
ER -