Resolvins: Firefighters In The Battle Against Chronic Inflammation

(Posted on Saturday, December 30, 2023)

This story is one of many exploring recent advances in the science of longevity and aging. Topics include musculoskeletal health, cognitive health, genetic predisposition to disease, inflammation, and many others. 

Inflammation is a complex, multi-step process. Like an elaborate domino setup, several different molecules need to act together to stimulate and direct the inflammatory response. Over the last two decades, researchers have become increasingly aware of an equally complicated inverse process: the resolution of inflammation. This, too, has its key players, known as specialized pro-resolving mediators (SPMs). Now, researchers at Albany Medical College have harnessed the power of these molecules to target the chronic, low-level inflammation associated with aging. Their work, published in The American Journal of Pathology, shows that treatment with specialized pro-resolving mediators can help combat, and potentially treat, “inflammaging”. 

Inflammaging: Too Much of a Good Thing?

Whenever you hurt yourself or get sick —whether it be a scraped arm, a viral infection, or a broken bone— you trigger your immune system’s inflammatory response. This a natural reaction to damage; it’s your body’s way of sending out alarm signals that attract healing immune cells to the area. The newly recruited cells help neutralize the threat and dispose of any injured tissue, enabling recovery. But a fine balancing act is required: although inflammation is vital to healing, too much of it, and you end up with unwanted collateral damage. Indeed, sometimes inflammation continues even after the external threat has been eliminated or the affected area has healed. This is known as chronic inflammation. Without a real target and without a stop signal, such inflammation begins to break down surrounding cells, tissues, and organs. 

Low-level, chronic inflammation of this type becomes increasingly common with age. Left to its own devices, it can lead to organ dysfunction. The liver is a clear example; it is one of the largest solid organs in our body and plays an important role in regulating both immunity and metabolism. It is also one of the organs for which age markedly increases the risk of scar-tissue formation, known as fibrosis. Fibrosis interferes with the liver’s ability to perform its routine tasks. In severe cases, it can lead to liver failure and death. The liver is also prone to getting “fatty” over time, which again hampers normal function. This is mostly seen in middle-aged and older adults. 

Inflammaging, then, presents a unique challenge: since older adults tend to have weakened immune function, it is important to find ways of resolving inflammation without simultaneously compromising the immune system’s ability to defend against threats. Corticosteroids, for example, just don’t cut it — these work by suppressing the immune response as a whole. 

Deciphering the Messages: RvD2-GPR18 Signaling  

To test novel therapeutic contenders, the researchers set out to deepen their understanding of the various factors involved in the resolution of inflammation. They homed in on a growing class of signaling molecules called specialized pro-resolving mediators (SPMs), which recent studies indicate are intimately linked to the regulation of inflammation. Specialized pro-resolving mediators work by attaching themselves to immune cells known as macrophages and guiding them to shift gears from a state that promotes inflammation into one that resolves it and repairs damaged tissue. 

These molecules were first discovered back in 2002 by Charles N. Serhan, PhD, DSc, and his laboratory at Harvard Medical School. Before then, most scientists studying inflammation focused on the “engine” of inflammation — the pathways and molecules that stimulate the inflammatory response. Dr. Serhan, and his mentee and colleague Bruce D. Levy, MD, ushered in a paradigm shift: instead of focusing on the engine driving inflammation, they moved their attention to the molecular “brakes” that help slow it back down. Previously, it was thought inflammation naturally subsides when the engine “runs out of gas”, but their work showed that the resolution of inflammation is a separate process with its own key players and pathways. 

Dr. Gabrielle Fredman, senior author of the latest study, was also a mentee and colleague of Dr. Serhan. Now a tenured professor at Albany Medical College, she spearheads a laboratory of her own. The Fredman lab continues to explore the nuanced processes involved in the resolution of inflammation, particularly as it relates to aging and cardiovascular disease. 

Resolvin D2 (RvD2) is one of the many specialized pro-resolving mediators currently known. It binds to a receptor found on the surface of macrophages, G protein-coupled receptor 18 (GPR18). By binding to this receptor, Resolvin D2 can influence the ingestion of bacteria or other harmful material and the production of inflammatory proteins called cytokines. Critically, it manages to boost immunity, boost tissue repair, and tame inflammation all without suppressing the host immune system. The relevance of the RvD2-GPR18 signaling pathway in aging, however, remained unclear. 

By screening macrophages sourced from the livers of old mice and elderly human adults, the researchers at Albany Medical College noticed a clear uptick in the expression of the gene that encodes the GPR18 protein. This was associated with both “fatty” liver and fibrosis in middle-aged and old mice. That said, mice engineered to lack the GPR18 receptor on the surface of monocytes and macrophages displayed increased liver fattiness and also increased scarring, suggesting the elevated expression of the gene may be a protective factor: it is expressed more highly in older mice and humans because it helps lessen the impact of inflammation. 

This was further confirmed by the fact that treatment of middle-aged mice with Resolvin D2 reduced the accumulation of liver fat and scar tissue. Resolvin D2 treatment also helped “ready the troops” by acting directly on bone marrow —the birthplace of all the body’s blood cells, including many immune cells— as evidenced by a rise in the numbers of macrophages and monocytes in the liver and blood. Resolvin D2 even managed to hold off the onset of liver damage following bone marrow transplantation from old mice into young mice, which usually leads to fibrosis and liver damage. 

Takeaways

Inflammation is a serious threat to longevity and healthy aging. It increases with age and is closely associated with tissue and organ damage. Unfortunately, we do not currently have any real treatment options to reduce chronic inflammation in older adults without also suppressing their immune systems. As things stand, it’s zero-sum: any gains in the resolution of inflammation are balanced out by losses in immune function. These latest findings suggest that Resolvin D2 may offer a potential solution. By targeting the GPR18 receptor on macrophages, the molecule helps reduce inflammation while still upholding proper immune function. If it works on the liver, it should also work on other organs and tissues — time, and additional research, will tell.

This article was originally published on Forbes and can be read online here.