Ciencias Exactas y Ciencias de la Salud

Irisin is a novel peptide hormone released from skeletal muscle following acute bouts of physical exercise. Besides its originally described role on adipose tissue browning, its direct antiinflammatory properties have been recently described. Specifically, when murine RAW264.7 macrophages were pre-treated with irisin, both gene and protein expression of key proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6, decrease following exposure to lipopolysaccharide (LPS), while levels of the anti-inflammatory cytokine IL-10 increase. These changes have been linked to decreased TLR4 protein expression and activity of NF-ΚB. As well, in murine models, irisin has been described to favor an alternatively activated M2 macrophage phenotype, both from a M0 unstimulated state and a M1 classical proinflammatory state. Recently, the importance of an anti-inflammatory microenvironment to maintain the differentiation and function of brown adipose tissue has been emphasized in preclinical models, which could imply that irisin exerts its global metabolic effects indirectly through its action on adipose tissue macrophages, at least partially. Thus, irisin and its downstream pathways could represent a novel therapeutic target in type 2 diabetes mellitus (T2DM), a disease state characterized by a systemic low-grade proinflammatory state and lower circulating levels of irisin compared with healthy controls. In humans, evidence shows that M1 macrophage infiltrates in adipose tissue originate from circulating monocytes, but no studies have described the role of irisin on any type of human immune cell. Using monocyte-derived macrophages (MDMs) obtained from peripheral blood mononuclear cells (PBMCs) from a previously characterized cross-sample of pediatric T2DM patients (n=15) and matched healthy controls (n=8), we sought to determine differences in MDM immunophenotypes between groups, their response to in vitro treatment with recombinant human irisin, and to correlate patients’ basal monocyte subsets with their clinical and biochemical parameters and MDM phenotypes. In order to standardize the procedures previous to testing cryopreserved samples of T2DM and control pediatric patients, blood was obtained from one healthy adult individual. In this subject, in vitro irisin treatment significantly increased CD163 MFI. T2DM subjects had higher proportions of circulating intermediate monocytes (IMs) relative to healthy controls, which correlated positively with body fat percentage and the inflammatory marker hs-CRP and negatively with HDL-c. MDMs from T2DM subjects had similar polarization profiles compared with controls when exposed to IL-4 and IFN-γ and LPS. However, macrophage polarization capacity, as measured by M1 (CD80) and M2 (CD163, CD200R) marker MFI, was significantly associated with basal monocyte proportions when considering all participants. Upon irisin treatment, CD163 upregulation was no longer observed in MDMs from patient samples, but a trend towards decreased NF-κB activation was noted. Our results provide preliminary evidence in favor of irisin’s anti-inflammatory role in human macrophages but must be replicated in future studies with larger sample sizes. On the other hand, increased IMs in pediatric T2DM might suggest enhanced monocyte migration and differentiation to macrophages in obese white adipose tissue or to vascular atherosclerotic lesions early in disease evolution, which warrants future longitudinal and mechanistic studies.

Ciencias Exactas y Ciencias de la Salud

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