New Findings Reveal Important Insights into Age-Related Nonresolving Inflammation

Aging is associated with chronic, nonresolving inflammation, or “inflammaging,” that can lead to tissue dysfunction. The resolution of inflammation is an active process that is governed by numerous factors, such as specialized proresolving lipid mediators (SPMs). Recent studies suggest that inflammaging may persist due to an impairment in inflammation-resolution programs and that treatment with SPMs, like resolvins, tempers excessive inflammation and age-related tissue dysfunction.

To explore SPM-initiated mechanisms that limit features of inflammaging, researchers conducted a novel series of studies using the ligand, or chemical messenger, Resolvin D2 (RvD2). RvD2 acts via a specific G-protein-coupled receptor called GPR18, which investigators found was associated with maintaining tissue homeostasis during aging.

Using mice to model normal, healthy aging, investigators identified key pathologic changes in the liver that occur in middle-age, including steatosis (fatty liver disease) and collagen deposition.

They observed that these changes correlated with a reduction in pro reparative (protective) macrophages.

Because transcriptional analysis showed that Gpr18 was increased in aged macrophages relative to young, they investigated its role in aging by generating a conditional knockout mouse wherein only myeloid cells lack GPR18 and through treatment of mice with GPR18’s ligand, RvD2.

Together, their studies demonstrated that myeloid-specific GPR18 limited steatosis and collagen accumulation in the liver.

Furthermore, adding RvD2 from an external source to activate GPR18 improved liver histopathology.

They also found that RvD2 treatment increased bone marrow and blood monocytes, as well as their precursors.

To examine how bone marrow function contributed to liver pathology they conducted bone marrow transplants in which they reconstituted young mice with the marrow from either young or old animals, with or without RvD2 treatment.

Dr. MacNamara noted, “These studies revealed that donor marrow from aged animals was sufficient to induce collagen accumulation in the liver, demonstrating that aging bone marrow contributes to liver pathology. Importantly, however, this could be improved with RvD2 treatment.”

Dr. Fredman commented, “Together, these studies demonstrate that RvD2-GPR18 signaling controls steatosis and fibrosis and provides a mechanistic-based therapy for promoting liver repair in aging.”

The investigators concluded that these studies provide a proof-of-concept that RvD2 can alleviate established liver scarring or fibrosis, for which there is currently no treatment, and that its action may in part be due to regulation of bone marrow.

According to Dr. MacNamara, “These studies reveal a potential therapy that may improve pathologies associated with aging by improving the process of blood cell production. The idea that bone marrow production can be modulated to generate cells that provide reparative functions may be broadly relevant in aging. Our studies not only highlight the remarkable durability of even transient treatment with RvD2, but they demonstrate the important role of bone marrow and its function in blood cell generation as a key aspect to treating disease. We believe there is tremendous promise of specialized proresolving lipid mediators, like RvD2, as therapies that may improve or augment current treatments.”

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Sources:

Hannah Fitzgerald, Jesse L. Bonin, Sayeed Khan, Maya Eid, Sudeshna Sadhu, Allison Rahtes, Masharh Lipscomb, Nirupam Biswas, Christa Decker, Melisande Nabage, Ramon Bossardi Ramos, Giesse Albeche Duarte, Michael Marinello, Anne Chen, Hasan Basri Aydin, Hebe Agustina Mena, Kurrim Gilliard, Matthew Spite, C. Michael DiPersio, Alejandro P. Adam, Katherine C. MacNamara, Gabrielle Fredman. Resolvin D2–G-Protein Coupled Receptor 18 Enhances Bone Marrow Function and Limits Steatosis and Hepatic Collagen Accumulation in Aging. The American Journal of Pathology, 2023; 193 (12): 1953 DOI: 10.1016/j.ajpath.2023.08.011

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Elsevier. “New findings reveal important insights into age-related nonresolving inflammation.” ScienceDaily. ScienceDaily, 6 December 2023. <www.sciencedaily.com/releases/2023/12/231206115858.htm>.

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