Abstract
Metabolic alterations induced by unhealthy lifestyles, including obesity and insulin resistance are often associated with increased innate immune response and chronic inflammation. Cholesterol has been identified as a key metabolite driving the activation of the inflammasome and the "epigenetic memory" in long-term living hematopoietic stem cells. In addition to these mechanisms, the physiological aging of short-living neutrophils is a relevant modifier of their immune competency, as while they egress from medullary niches as "fresh", fully competent, cells, they turn into "aged", disarmed cells, when they extravasate into peripheral tissues to fight against pathogens or they reach the spleen for disposal. We recently observed that cardio-metabolic alterations induced by a lipid enriched unhealthy diet critically accelerate this process. Indeed, the chronic feeding with a high fat diet (HFD) results in the increase of aged neutrophils in the circulation and their accumulation in liver. This profile is associated with a deteriorated insulin response and obesity. The HFD primes aged, but not fresh neutrophils, to infiltrate in the liver and promotes inflammation coupled to altered cell immune architecture in visceral adipose tissue. Preventing the aging of neutrophils via selective ablation of CXCR2, reduces the development of obesity and improves the sensitivity to insulin. In humans, plasma levels of CXCL1, one of the cytokines binding CXCR2 and promoting neutrophil aging, are directly associated with abdominal adiposity and fatty liver independently of other risk factors. Together these findings point to a direct role of aged neutrophils in the development of metabolic disorders.