Chronic Activation of cGAS-STING in Aged Macrophages Reduces Normal STING Response to Pathogens
In aged cells, mitochondrial dysfunction leads to mislocalization of mitochondrial DNA fragments to the cytosol. There, innate immune defenses such as the cGAS-STING pathway react to the mitochondrial DNA in much the same way as they would react to bacterial or viral sequences, provoking inflammatory signaling. This is a bad thing, a maladaptive response that contributes to age-related disease and loss of function. Here, researchers show that this chronic stimulation of the cGAS-STING pathway degrades the normal, useful response of STING to the presence of pathogens, thereby contributing to the age-related loss of immune defenses against infection. This theme, chronic inflammation interfering in useful short-term inflammatory responses, is seen throughout the aged immune system.
Ageing is a major risk factor that contributes to increased mortality and morbidity rates during influenza A virus (IAV) infections. Macrophages are crucial players in the defense against viral infections and display impaired function during ageing. However, the impact of ageing on macrophage function in response to an IAV infection remains unclear and offers potential insight for underlying mechanisms. In this study, we investigated the immune response of young and aged human monocyte-derived macrophages to two different H1N1 IAV strains.
Interestingly, macrophages of aged individuals showed a lower interferon response to IAV infection, resulting in increased viral load. Transcriptomic data revealed a reduced expression of stimulator of interferon genes (STING) in aged macrophages albeit the cGAS-STING pathway was upregulated. Our data clearly indicate the importance of STING signaling for interferon production. Evaluation of mitochondrial function during IAV infection revealed the release of mitochondrial DNA to be the activator of cGAS-STING pathway. The subsequent induction of apoptosis was attenuated in aged macrophages due to decreased STING signaling.
Our study provides new insights into molecular mechanisms underlying age-related immune impairment. To our best knowledge, we are the first to discover an age-dependent difference in gene expression of STING on a transcriptional level in human monocyte-derived macrophages possibly leading to a diminished interferon production.