A role of STING signaling in obesity-induced lung inflammation

Abstract

Background It is established that pulmonary disorders are comorbid with metabolic disorders such as obesity. Previous studies show that the stimulator of interferon genes (STING) signaling plays crucial roles in obesity-induced chronic inflammation via TANK-binding kinase 1 (TBK1) pathways. However, it remains unknown whether and how the STING signaling is implicated in the inflammatory processes in the lung in obesity. Methods Human lung tissues were obtained from obese patients (n = 3) and controls (n = 3). Mice were fed with the high-fat diet or regular control diet to establish the diet-induced obese (DIO) and lean mice, and were treated with C-176 (a specific STING inhibitor) or vehicle respectively. The lung macrophages were exposed to palmitic acid (PA) in vitro. The levels of STING singaling and metabolic inflammation factors were detected and anlyzed. Results We find that STING+/CD68+ macrophages are increased in lung tissues in patients with obesity. Our data also show that the expressions of STING and the levels of proinflammatory cytokines are increased both in lung tissues and bronchoalveolar lavage fluid (BALF) in obesity compared to controls, and inhibition of the STING blunted the obesity-induced lung inflammation. Mechanistically, our data demonstrate that the STING signaling pathway is involved in the PA-induced inflammation through the STING-TBK1-IRF3 (interferon regulatory factor 3)/NF-κB (nuclear factor kappa B) pathways in the lung macrophages. Conclusions Our results collectively suggest that the STING signaling contributes to obesity-associated inflammation by stimulating proinflammatory processes in lung macrophages, one that may serve as a therapeutic target in ameliorating obesity-related lung dysfunctions.

Diabetes Mellitus, Energy Metabolism, and COVID-19

“…STING is considered to be a molecular connection between immunity and metabolism ( 116 ). Activation of STING in obesity increases the pro-inflammatory capacity of lung macrophages, a potential mechanism underlying obesity-related lung inflammation ( 117 ). Notably, STING is a major contributor to the aberrant type I IFN response in COVID-19, which amplifies the inflammatory response during the late phase of SARS-CoV-2 infection ( 118 ).…”

Linking Adiposity to Interstitial Lung Disease: The Role of the Dysfunctional Adipocyte and Inflammation

“…The stimulator of interferon genes, also known as STING, is a protein expressed in the endoplasmic reticulum [ 102 ]. STING is upregulated in the setting of lung damage, including in pulmonary fibrosis and acute infection [ 102 ].…”

“…The stimulator of interferon genes, also known as STING, is a protein expressed in the endoplasmic reticulum [ 102 ]. STING is upregulated in the setting of lung damage, including in pulmonary fibrosis and acute infection [ 102 ]. Excess adiposity may enhance the expression of STING, resulting in increased downstream TNF-α, IL-6, and IFNβ production in lung tissues [ 102 ].…”

“…STING is upregulated in the setting of lung damage, including in pulmonary fibrosis and acute infection [ 102 ]. Excess adiposity may enhance the expression of STING, resulting in increased downstream TNF-α, IL-6, and IFNβ production in lung tissues [ 102 ]. The mechanism for obesity-mediated increased STING appears to be a result of increased mitochondrial DNA leakage, as obese mouse models have increased mitochondrial DNA leakage into the cytosol through imbalanced levels of disulfide-bond A oxidoreductase-like protein [ 103 ].…”

Obesity-induced downregulation of miR-192 exacerbates lipopolysaccharide-induced acute lung injury by promoting macrophage activation

“…Effectively interrupting the lung inflammation cascade and alleviating lung injury can be achieved by inhibiting the pro-inflammatory M1 polarization of macrophage [ 11 ]. Increasing evidence suggests that, in the context of obesity, lung tissue macrophages are extensively recruited and polarized towards a pro-inflammatory state, ultimately leading to lung inflammation [ 9 , 12 , 13 ]. Consequently, targeting macrophages presents a promising avenue for new therapeutic strategies to address obesity-related ALI.…”