Towards More Selective Ways to Block Unwanted Inflammation
Control of chronic inflammation may turn out to be one of the more important themes in the treatment of aging as a medical condition. Senescent cells generate inflammatory signaling, but removing that contribution is likely the easiest aspect of the problem. Many forms of age-related cellular damage and dysfunction generate constant, unwanted, excess inflammation through interactions and signals that are used during a normal, desirable inflammatory reaction, such as to injury or infection. Thus interfering in these mechanisms must be very selective; simply blockading a given signal has undesirable side-effects, such as a weakening of the immune response. A fair amount of the research aimed at producing more selective anti-inflammatory treatments is focused on STING, as many pro-inflammatory mechanisms associated with age and disease involve this protein, and it can act in many different ways. As researchers note here, perhaps this is a place to start in the search for better approaches to dampening the chronic inflammation of aging.
A type of T cell known as an effector memory T cell (Tem) can become a critical driver of cytokine storms. The chain reaction appears to start when Tem cells interact with dendritic cells, which serve as the immune system's primary detector of viral and bacterial invasions. When the immune system wins the battle, most of the custom T cells stand down. But a few guards linger in the blood and other body tissues to be ready to "effect" a rapid response should the same type on infection occur again. Hence the name effector memory T cells.
However, ongoing encounters with Tem cells, such as those occurring when people have autoimmunity or live in a state of chronic inflammation, actually cause DNA strands within dendritic cells to break. This, in turn, prompts a DNA repair pathway that rapidly generates large numbers of inflammatory cytokines, including IL-1b, IL-6, and IL-12. This flood, or storm, of cytokines causes the tissue damage that occurs in autoinflammatory diseases including type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel diseases like Crohn's disease. For some people with these conditions, ongoing inflammation also increases their risk of developing cancer.
Researchers detected upregulation of expression of Tmem173 in dendritic cells following interactions with Tem cells. Tmem173 which encodes for stimulator of interferon genes (STING). The STING pathway has been described in previous research as being important to detect viral infections. But when Tem cells harm dendritic cells, the STING pathway does not follow the same route that it typically does when directly responding to viral infections. In this situation, STING teams up with the gene TRAF6 and the transcription factor NFkB to form an "axis" of activity that drives runaway production of innate inflammatory cytokines.
The researchers further reasoned that if they could prevent STING and TRAF6 from working together, they could cut off the inflammation chain reaction at an early stage. In mice gene-edited to lack the STING pathway, that's exactly what they found. When treated with a drug known to induce an intense T cell-mediated inflammatory response, these mice did not produce a flood of innate cytokines. The mouse study involved a whole-body elimination of STING. Attempting the same in humans would not be advisable because STING is used by a number of cell types outside the immune system in necessary ways. "Our goal will be to develop a highly focused method or methods for blocking STING within targeted immune cells, without disrupting its other important functions. If we can achieve that, we may have a powerful new tool for controlling hyper-inflammation."