The aging of neutrophils is critical for high fat diets-induced metabolic alterations

Background and Aims: Highly caloric-induced chronic metabolic alterations perpetuate constitutive hyper-activation of myeloid cells precursors. Neutrophils physiologically age during their short lifetime, after being released “fresh” from bone marrow (BM) and during their canonical activity against external invaders. We here studied how neutrophil plasticity and aging are affected by unhealthy diets, how this impacts neutrophil infiltration in inflamed metabolic tissues and the metabolic outcomes. Methods: Our experimental models were: wild-type mice (WT) on HFD and chow diet, mice with constitutively aged (CXCR4fl/flCre+) or fresh neutrophils (CXCR2fl/flCre+) (neutrophil-specific deletion of CXCR4/CXCR2 by Cre recombinase on MRP8) HFD-fed for 20 weeks, and we: immunophenotyped neutrophils and their hematopoietic progenitors in tissues, assessed their systemic metabolic response, histologically characterized their metabolic tissues. Results: HFD increased granulopoiesis in BM (1,3*104±2,6*103 vs 5,3*103±2,1*103 cells/leg, p=0,003), the number of circulating neutrophils (2,7*102±0,88*102 vs 1,39*102±0,69*102 cells/μL, p=0,012), and those homed in liver (5,4*105±2,6*105 vs 6,55*102± 7,29*102 cells/g, p<0,001) and in visceral adipose tissue (VAT) (6,7*104±2,4*104 vs 5,57±8,3 cells/g, p<0,001) in WT mice. Besides, CXCR2fl/flCre+ neutrophils infiltrated less in liver (2,5*105±3,3*105 vs 1,3*106±6,5*105 cells/g, p=0,006), and in VAT (2,5*104± 1,1*104 vs 1,8*105± 1,0*105cells/g, p=0,043) versus CXCR4fl/flCre+. Metabolically, these different profiles resulted into more hepatic steatosis and accumulation of inflammatory macrophages (M1) in VAT of CXCR4fl/flCre+ versus CXCR2fl/flCre+, while CXCR2fl/flCre+ were less obese, displayed less hepatic steatosis and showed greater reduction of glycaemia after insulin administration versus WT (glycaemia decrease after insulin -152,52± 31,35 vs -48,6± 43,76 iAUC, p=0,002). Conclusions: The aging of neutrophils could contribute to the development of HFD-induced metabolic alterations.