Sterile Lung Inflammation Induced by Silica Exacerbates Mycobacterium tuberculosis Infection via STING-Dependent Type 2 Immunity

Abstract

Graphical Abstract Highlights d Silica impairs host control of M. tuberculosis infection via a type 2 immune response d Extracellular DNA potentiates silica-induced exacerbation of M. tuberculosis infection d Silica primes STING activation, potentiating the response to M. tuberculosis DNA d Both host and M. tuberculosis DNA trigger cGAS/STING/ IFNI-mediated type 2 immunity SUMMARY Lung inflammation induced by silica impairs host control of tuberculosis, yet the underlying mechanism remains unclear. Here, we show that silicadriven 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.

Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage

“…We found that microglia were significantly activated and polarized into M1 phenotype after SAH, as evidenced by the morphological changes and increased level of microglial M1 markers CD16, IL-1β, iNOS, IL-6, TNF-α, and NLRP3 inflammasome. Similar to previous literature demonstrating the effect of STING in modulating macrophage polarization [49,50], our data indicated that activation of STING could enhance inflammatory response through promoting microglial activation and polarizing into pro-inflammatory M1 phenotype. And treatment with C-176 significantly inhibited STING-mediated neuroinflammation after SAH.…”

“…Meanwhile, the M2 phenotype microglia were identified to release anti-inflammatory and neuroprotective effects via secreting anti-inflammatory cytokines and promoting neural regeneration, oligodendrogenesis, and angiogenesis [48]. Notably, recent studies demonstrated that activation of STING could repolarize macrophages from M2 phenotype into M1 phenotype in a disease model of tuberculosis infection and colitis [49,50].…”

Interleukin-2-Inducible T-Cell Kinase Deficiency Impairs Early Pulmonary Protection Against Mycobacterium tuberculosis Infection

“…In humans, Mtb infects via inhalation of a low dose of aerosolized bacteria; therefore, low-dose aerosol inoculation would better mimic the nature of Mtb infection in humans. However, in the absence of the ability to perform aerosolized infections, the standard experimental protocol of Mtb infection in mice is 1,000 CFU via intranasal inoculation (69)(70)(71)(72). Monocytes play an essential role in initiating T-cell responses in the lung against Mtb infection (73), and using this standard protocol of Mtb infection in mice, we previously observed monocytosis (64), similar to what has been reported in other studies using aerosolized low-dose infection protocols (74,75).…”

Silica‐related diseases in the modern world: A role for self‐DNA sensing in lung inflammatory diseases

“…Indeed, host control of mycobacterial infection relies on type 1 immunity. However, we found that silica pre‐exposure activates the DNA/cGAS/STING pathway and increases the type 1 IFN response to mycobacterial infection that, in turn, enhances type 2 immunity and favours infection in mice 3 …”