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Age-associated accumulation of B cells promotes macrophage inflammation and inhibits lipolysis in adipose tissue during sepsis

ABSTRACT: Noncanonical lipolysis induced by inflammatory cytokines or toll-like receptor ligands is required for the regulation of inflammation during endotoxemia and sepsis. Canonical lipolysis induced by catecholamines declines during aging, but the extent to which the noncanonical pathway of lipolysis is active during aging remains unknown. The immune compartment of visceral white adipose tissue (vWAT) changes during aging, including an expansion of lymphocytes, pro-inflammatory macrophage polarization, and an increase in chronic low-grade inflammation, all of which influence canonical lipolysis in old vWAT. Therefore, we aimed to define the extent to which immune cells from older hosts influence noncanonical lipolysis induced by sepsis. Here we show that models of polymicrobial sepsis and lipopolysaccharide (LPS)-induced endotoxemia induce vWAT lipolysis in young mice but fail to activate lipolytic pathways in vWAT from old mice. Characterization of vWAT B cells revealed an accumulation of dysfunctional B1 B cells and an amplified inflammatory signature induced by LPS in old B1 B cells compared to old B2 B cells. Short term depletion of B2 B cells from old mice and adoptive transfer of peritoneal B cells from old mice into young recipient mice were insufficient to alter LPS-stimulated lipolysis. However, life-long deficiency of B cells increased LPS-stimulated lipolysis, suggesting the suppressive role of B cells may be indirect and requires other cell types. Pro-inflammatory macrophages and NLRP3 inflammasome activation were significantly reduced in the old B cell knockout mice. These data collectively reveal a decline in noncanonical lipolysis in vWAT during aging that is regulated by resident immune cells. Additionally, our study suggests the B cell-macrophage signaling axis may offer new approaches to resolve metabolic dysfunction in aged vWAT and attenuate septic severity in older individuals.

ORGANISM(S): Mus musculus

PROVIDER: GSE250371 | GEO | 2024/03/18

REPOSITORIES: GEO

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Project description:Sepsis is a severe and dysregulated inflammatory disease that often precedes the development of acute kidney injury (AKI) with consequent worsening outcome. The main characteristics of sepsis-induced AKI include endothelial cell (EC) dysfunction, infiltration of inflammatory cells, glomerular thrombosis, and renal tubular epithelial cells (RTEC) injury. Numerous studies have demonstrated that mammalian target of rapamycin (mTOR) activation has been implicated in the initiation and progression of renal injury in course of sepsis. However, little is known, about the molecular basis of mTOR role in EC and RTEC dysfunction. Here, we evaluate whether mTOR inhibition by Rapamycin (Rp) as potential strategy to ameliorate renal function and dissected the molecular mechanisms involved. In a mouse model of lipopolysaccharide (LPS)-induced AKI , LPS injection led to a time-dependent increase of serum creatinine and significant morphological changes in renal parenchyma associated with increased collagen deposits and endothelial dysfunction. Interestingly, Rp treatment significantly decreased creatine levels and preserved renal parenchyma, counteracting Endothelial-to mesenchymal transition (EndMT) process and early fibrosis through the inhibition of ERK pathway. Next, we examined the effects of LPS-TLR4 interaction in RTECs. Through a whole-genome DNA methylation analysis in cultured RTEC, we found that LPS induced aberrant methylation, particularly in regions involved in premature aging. The most represented genes were CD39 and WFS1. LPS stimulation of RTEC led to up-regulation of SA-β Gal and cell cycle arrest markers such as p21. In accordance, in endotoxemic mice, we found a decreased expression of CD39 concurrent with Klotho down-regulation. Administration of Rp exerted anti-aging effects in endotoxemic mice, preserving CD39 and Klotho expression. In conclusion, we demonstrated that mTOR inhibition could offer novel strategies to protect endothelial and tubular compartment from accelerated aging and fibrosis thus counteracting the progression to chronic kidney disease.

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Age-associated accumulation of B cells promotes macrophage inflammation and inhibits lipolysis in adipose tissue during sepsis

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