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Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis
Published on: June 3, 2016
GDF3 promotes adipose tissue macrophage-mediated inflammation via altered chromatin accessibility during aging
In Hwa Jang1,2,3, Anna Carey2,3,4, Victor Kruglov2
1Biochemistry, Molecular Biology, and Biophysics Graduate Program, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
Abstract:
Aging is characterized by amplified inflammation, including proinflammatory macrophages and increased susceptibility to endotoxemia. Here we uncover a mechanism by which macrophages maintain their inflammatory phenotype through autocrine GDF3-SMAD2/3 signaling, which ultimately exacerbates endotoxemia. We show that inflammatory adipose tissue macrophages display an age-dependent increase in GDF3, a TGFβ-family cytokine. Lifelong systemic or myeloid-specific Gdf3 deletion leads to reduced endotoxic inflammation. Using pharmacological interventions to modulate the GDF3-SMAD2/3 axis, we demonstrate its role in regulating the inflammatory adipose tissue macrophage phenotype and endotoxemia lethality in old mice. Mechanistically, single-cell RNA sequencing and assay for transposase-accessible chromatin with sequencing analyses suggest that GDF3 induces a shift toward an inflammatory state by limiting methylation-dependent chromatin compaction. Leveraging human adipose tissue samples and 11,084 participants from the atherosclerosis risk in communities study, we validate the relevance of GDF3 to aging in humans. These findings position the GDF3-SMAD2/3 axis as a critical driver of age-associated chromatin remodeling and a promising therapeutic target for mitigating macrophage-related inflammation in aging.
Insights
Aging increases inflammation and macrophage susceptibility to endotoxemia. This study reveals that GDF3-SMAD2/3 signaling drives this age-related inflammation, offering a potential therapeutic target.
Area of Science:
- Immunology
- Gerontology
- Molecular Biology
Background:
- Aging is associated with increased systemic inflammation and heightened susceptibility to infections like endotoxemia.
- Proinflammatory macrophages contribute significantly to age-related inflammatory conditions.
Purpose of the Study:
- To elucidate the mechanism by which macrophages maintain an inflammatory phenotype during aging.
- To investigate the role of Growth Differentiation Factor 3 (GDF3) and its signaling pathway in age-associated inflammation and endotoxemia.
Main Methods:
- Analysis of adipose tissue macrophages from aging mice and human participants.
- Genetic manipulation (Gdf3 deletion) and pharmacological inhibition of the GDF3-SMAD2/3 pathway.
- Single-cell RNA sequencing and ATAC-seq to study chromatin remodeling.
- Validation in a large human cohort (Atherosclerosis Risk in Communities study).
Main Results:
- An age-dependent increase in GDF3 was observed in adipose tissue macrophages.
- Deletion of Gdf3 reduced endotoxic inflammation and improved survival in aged mice.
- Modulation of the GDF3-SMAD2/3 axis regulated macrophage phenotype and endotoxemia lethality.
- GDF3 was shown to promote an inflammatory state by reducing methylation-dependent chromatin compaction.
- Human data confirmed the relevance of GDF3 in aging.
Conclusions:
- The GDF3-SMAD2/3 signaling axis is a key driver of age-associated inflammation by influencing macrophage phenotype and chromatin structure.
- Targeting the GDF3-SMAD2/3 pathway represents a promising therapeutic strategy for mitigating age-related inflammation and improving outcomes in conditions like endotoxemia.
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