Leukotrienes in diabetes type 1: Activation of a distinct immunometabolic phenotype in macrophages

Type 1 diabetes (T1D) is a metabolic disease characterized by hyperglycemia, hypoinsulinemia and dyslipidemia. This imbalance of nutrients leads to systemic inflammation known as meta -inflammation and comorbidities linked to DT1. Leukotrienes are lipid mediators shown to contribute to the establishment of systemic inflammation in DT1 and also to the inflammatory phenotype in macrophages in this condition. In addition, leukotrienes contribute to the increase in mitochondrial oxidative metabolism in macrophages in an uncoupling protein UCP1-associated manner. However, which metabolic pathways and their role for the function of macrophages in DT1 had never been studied. Herein, we showed that the fatty acid oxidation path associated with the activity of the uncoupling protein UCP1 is important for the activation of peritoneal macrophages in DT1. We have shown that leukotrienes contribute to pro-inflammatory phenotype but with traces of reparative phenotype and these cells have high oxidative metabolism associated with high expression of the UCP1 uncoupling protein. The production of cytokines IL-12, IL-1 and IL-10 elevated in diabetic macrophages in a leukotriene-dependent manner, came down dramatically after blocking fatty acid oxidation by the drug Etomoxir, indicating the important role of this pathway in the activation of macrophages. As evidence of this, in vitro assays have shown that UCP1 protein expression in macrophages increases in a leukotriene-dependent manner when these cells are placed in conditioned medium derived from lipolysis. Finally, we show that leukotrienes contribute to metaflammation by inducing inflammation in the epididimal adipose tissue, intensifying the loss of adiposity in diabetic animals. Our results indicate an important role of leukotrienes in the activation and immunometabolic condition of peritoneal macrophages in addition to the establishment of systemic inflammation of DT1 (AU)