Targeting the cGAS-STING pathway to Sabotage Chronic Inflammation
Chronic inflammation is a major issue in aging. The immune system reacts inappropriately to rising levels of molecular damage, spurred on by the pro-inflammatory signaling of growing numbers of senescent cells, and enters a state of continual overactivation. This broadly disrupts cell and tissue function throughout the body in many ways. Present approaches to reducing inflammation, largely deployed as treatments of autoimmune conditions, involve the brute force sabotage of important inflammatory signaling pathways such as those involving tumor necrosis factors. This can achieve the goal of reducing chronic inflammation, but at the cost of also sabotaging some of the vital work of the immune system in defending against pathogens and destroying errant cells.
Are there similar brute force approaches that can sabotage immune system signaling pathways that are less involved in vital work and more involved in inappropriate overactivation in old age and autoimmunity? That might be the case. The cGAS-STING pathway is attracting a great deal of research interest of late, and may prove to be a better option than tumor necrosis factor interactions, but it is still involved in the detection of pathogens and problematic cells. A better class of approach might be to instead address the causes of inflammation: the senescent cells, the cell damage, the reasons why the signaling environment shifts to be more inflammatory.
The cGAS-STING pathway as a therapeutic target in inflammatory diseases
The detection of foreign DNA serves as a crucial element of immunity in many organisms. In mammalian cells, this task is contributed in large part by the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which has emerged as a critical mechanism for coupling the sensing of DNA to the induction of powerful innate immune defence programmes. Within this pathway, the binding of cGAS to double-stranded DNA (dsDNA) allosterically activates its catalytic activity and leads to the production of 2′3′ cyclic GMP-AMP (cGAMP), a second messenger molecule and potent agonist of STING.
A salient feature of the cGAS-STING pathway, which sets it apart from several other innate immune signalling mechanisms, is that its activation is triggered by a fundamental element of life (namely DNA) and, therefore, lacks any pathogen-specific attributes. For this reason, cGAS recognizes a broad repertoire of DNA species of both foreign and self origin. Today, our understanding of the diverse functions of the cGAS-STING pathway in host immunity has become clearer, and multiple examples highlight the protective effects of this pathway during infection. Recent studies showing that the cGAS-STING system arose from an ancient bacterial anti-phage mechanism underscore this notion.
Growing evidence has indicated, however, that dysregulation of this highly versatile innate immune sensing system can disrupt cellular and organismal homeostasis by fuelling aberrant innate immune responses associated with a number of pathologies. The parameters that dictate host-protective versus pathogenic activity are still being unfolded, but it appears that the intensity and chronicity of cGAS-STING signalling are major determinants in most cases. In light of this, efforts have been undertaken or are still under way to define strategies that allow selective modulation of cGAS-STING activity in various disease settings.
A critical aspect for the future will be to better understand the minimal level of inhibition required for therapeutic benefit. It is possible that strong reduction of the pathway provokes adverse effects in humans by increasing susceptibility to infection. This may be particularly relevant for the treatment of chronic conditions that require repetitive or continuous treatment regimens. Still, the direct targeting of cGAS-STING bears potential benefits over more non-specific and broadly acting anti-cytokine antibodies or compounds targeting key signalling molecules, such as JAK inhibitors or TBK1 inhibitors, as it leaves intact essential compensatory innate immune recognition pathways, most critically the TLR, RIG-like receptor, and inflammasome pathways.
No mention of transposons in the review? Multiple studies have now shown their derepression with age and their ability to activate the cGAS-STING pathway.