The aging of neutrophils is actively involved in the metabolic consequences of high fat diet

Abstract

Aim: The epigenetic modifications induced by High Fat Diets (HFDs) in long-living hematopoietic cells have been well described, but whether they affect the “aging” of neutrophils, characterized by far shorter half-life, is less clear. Neutrophils "age" through a reciprocal regulation of CXCR4, promoting a "fresh" status when leaving the BM, and CXCR2, accelerating their aging in the circulation. We study whether derailed aging exacerbates the metabolic and inflammatory consequences of HFD.
Methods: We immunophenotyped neutrophils and characterized the metabolic responses in physiology (wild-type mice, WT) and in mice with either constitutively aged neutrophils (MRP8 driven conditional deletion of CXCR4; herein CXCR4fl/flCre+) or with constitutively fresh neutrophils (MRP8 driven conditional deletion of CXCR2; CXCR2fl/flCre+), following 20 weeks of HFD feeding (45% Kcal from fat).
Results: CXCR4fl/flCre+ mice display higher plasma triglycerides levels versus WT, despite comparable glucose levels, when monitored during standard feeding. This metabolic difference was exacerbated by feeding mice a HFD for 20 weeks. Indeed, despite a comparable gluco-metabolic profile between CXCR4fl/flCre+ and WT mice, liver damage was increased in CXCR4fl/flCre+, linked to the higher accumulation of CXCR4fl/flCre+ neutrophils in the liver after 20 weeks and two hours after intragastric gavage with olive oil versus fasting. As this finding was not observed after 20 weeks of standard fat diet, these results suggest that HFD feeding redirects aged neutrophil to the liver, resulting in enriched oxidative metabolism and NETosis- and inflammation-related pathways in the liver of CXCR4fl/flCre+ mice.
Conversely, CXCR2fl/flCre+ mice were protected from obesity and insulin resistance, exhibiting a proresolutive phenotype.
In humans, increased plasma levels of Cxcl1 (ligand of CXCR2) correlated with visceral obesity and metabolic syndrome.
Conclusions: Neutrophil aging might contribute to the cardio-metabolic consequences of HFD. This aging could represent a new therapeutic target beyond the current anti-inflammatory therapies approved for the treatment of cardiovascular diseases.