The innate immune system becomes increasingly inflammatory with age, in part due to damage and dysfunction in immune cells, in part a maladaptive reaction to a damaged environment. Chronic inflammation is disruptive to tissue structure and function. Macrophages make up a sizable fraction of the innate immune system, resident in tissues and involved in both tissue maintenance and defense against pathogens. A broad range of research is focused on better understanding and potentially manipulating macrophage behavior to obtain desired outcomes, such as a lower level of chronic inflammation in later life.
In today's open access paper, researchers focus on the macrophages resident in fat tissue. Visceral fat is a source of inflammation, and this is one of the reasons why being overweight is increasingly bad for health as life progresses into older age. This research illuminates one of the regulatory elements involved in increasing inflammatory behavior in macrophages in fat tissue, raising its profile as a potential target for anti-inflammatory therapies, and contributing to the bigger picture of inflammatory mechanisms in visceral fat tissue.
Older individuals have increased risk for infections and subsequent sepsis, in part owing to accumulating adiposity and a dysfunctional immune system. Gerotherapeutics that successfully improve the aged immune response are largely understudied. Our study reveals that the GDF3-SMAD2/3 axis may be a relevant pharmacologic target. GDF3 promotes the inflammatory phenotype of adipose tissue macrophages, contributing to the exacerbation of endotoxemia-induced inflammation in older, but not younger, organisms. GDF3 signals through SMAD2/3 and elicits proinflammatory responses in adipose tissue macrophages, diverging from their canonical immunoregulatory function.
Specifically, the chromatin landscape of adipose tissue macrophages shifts toward inflammation with age, increasing the accessibility of inflammation-associated genes. Our study demonstrates that Gdf3 deficiency can reverse the age-dependent changes in chromatin accessibility and transcription by restoring H3K27me3 levels in adipose tissue macrophages. Furthermore, genetic and pharmacological inhibition targeting the GDF3-SMAD2/3 axis protects against endotoxemia-induced inflammation and lethality in old mice.
The importance of visceral adipose tissue (VAT) in aging and inflammation is corroborated by studies that highlight the immunological role of VAT during metabolic challenge or infection in older organisms. Recent work indicates that B cells-derived IgG elevates macrophage expression of Tgfb, which promotes fibrosis and metabolic decline via SMAD2/3 in aged VAT. Our work builds on this model, providing additional evidence for the importance of B cell-macrophage crosstalk in VAT. We also provide evidence for the GDF3-SMAD2/3 axis regulating the phenotype of B cells. Although it remains unclear whether GDF3 acts synergistically with TGFβ-superfamily cytokines, our findings indicate that the mechanism governing inflammatory VAT microenvironment, driven by adipose tissue macrophages and B cells, may converge on SMAD2/3 signaling.
View the full article at FightAging
