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Published on: April 3, 2017
cGAS-STING signaling is blunted in senescent macrophages and monocytes in obesity
Carine Raquel Richter Schmitz1, Lucas Kich Grun2, Bruno Kendi Makiyama3
1Graduate Program in Biological Sciences: Biochemistry, Federal University at Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Group of Inflammation and Cellular Senescence, Immunobiology Laboratory, School of Health Sciences and Life, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.
Introduction:
The cGAS-STING pathway is essential for immunity, detecting cytosolic DNA to trigger defense mechanisms and sterile inflammation linked to aging, obesity, and chronic inflammatory diseases. This study examines cGAS-STING signaling in senescent monocyte-derived macrophages (MDMs) and monocytes within the context of obesity.
Materials And Methods:
Primary human MDMs were differentiated from peripheral blood of young, healthy, lean donors using M-CSF, to guide monocytes toward the macrophage lineage. MDMs were cultured for 7 or 21 days to induce replicative senescence. Peripheral monocytes were also isolated from age- and sex-matched lean and obese participants.
Results:
MDMs cultured for 21 days exhibited increased cellular and nuclear area, developed a senescent phenotype marked by increased P16 expression and γH2AX phosphorylation, shorter telomeres, loss of LAMIN B1, diminished phagocytosis, with reduced STING expression and impaired response to cGAS agonist 2'3'-cGAMP. Similarly, ex vivo monocytes from individuals with obesity displayed elevated P16 expression and increased γH2AX and β-galactosidase activity, along with increased STING expression, compromised downstream signaling and reduced cytokine secretion.
Discussion:
Dysfunctional cGAS-STING signaling and senescence markers suggest a shared mechanism underlying immune dysfunction in aging and obesity. Understanding cGAS-STING's role in immune cells may provide insights into age-related immune decline and chronic inflammation.
Insights
The cGAS-STING pathway shows dysfunction in senescent cells and those from individuals with obesity, indicating a shared mechanism for immune issues in aging and obesity. This impacts immune defense and inflammation.
Area of Science:
- Immunology
- Cellular senescence
- Metabolic disease
Background:
- The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is crucial for innate immunity and sterile inflammation.
- Dysregulation of this pathway is implicated in aging, obesity, and chronic inflammatory conditions.
Purpose of the Study:
- To investigate the cGAS-STING signaling pathway in senescent monocyte-derived macrophages (MDMs) and monocytes from individuals with obesity.
- To explore potential shared mechanisms of immune dysfunction in aging and obesity.
Main Methods:
- Human MDMs were differentiated and cultured to induce replicative senescence.
- Monocytes were isolated from lean and obese participants.
- Senescence markers (P16, γH2AX, β-galactosidase), telomere length, LAMIN B1, phagocytosis, STING expression, and cGAS-STING pathway responses were assessed.
Main Results:
- Senescent MDMs exhibited hallmarks of senescence, reduced STING expression, and impaired cGAS-STING signaling.
- Monocytes from individuals with obesity showed increased senescence markers, elevated STING expression, compromised downstream signaling, and reduced cytokine secretion.
Conclusions:
- Dysfunctional cGAS-STING signaling and senescence markers in immune cells suggest a common pathway contributing to immune dysfunction in aging and obesity.
- Understanding this pathway's role in immune cells offers insights into age-related immune decline and chronic inflammation.
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