Dovhyi R. Functional polarization of phagocytes and its correction in animals of different age groups

It is known that the vast majority of tissue-resident macrophages have embryonic origin. Preliminary research shows that macrophages of embryonic and monocytic origin change differently with aging. Many pathological states are associated with the inappropriate metabolic profile of macrophages. Recent studies showed that multipotent mesenchymal stromal cells (MMSC) are promising candidates in the treatment of immune-mediated disorders due to their ability to cause anti-inflammatory metabolic skew of leukocytes, including macrophages. However, the capability of MMSC to modulate metabolic state of macrophages of different origin from aged organism remains largely unexplored. The aim of the present study was the investigation of phenotypic and functional profile of phagocytes and its correction in mice of different ages. Age-related changes in the metabolic profile of murine phagocytes of different localization and ontogenetic origin were discovered and characterized for the first time. Macrophages of the monocytic origin (bone marrow-derived and splenic macrophages), obtained from aged mice were characterized by pro-inflammatory (M1) skew of arginine metabolism, while macrophages of embryonic origin (peritoneal and alveolar macrophages) exhibited anti-inflammatory skew of arginine metabolism (M2) accompanied by the decrease of oxidative metabolism. Current data concerning the effect of macrophages in lymphoid organ niche on age-related changes of T-lymphocytes were expanded exploiting heterochronic parabiosis model. Macrophages of aged mice were characterized by significantly higher migration rate into spleen and lymph nodes of the young animals. Increase in the macrophage fraction in the lymph nodes was associated with a higher number of T-lymphocytes with regulatory phenotype in this organ. However, migration of macrophages from aged animals into the spleen of young mice was accompanied by the decrease of regulatory T cells number. New data on the modulatory effect of MMSC on the metabolic profile of macrophages was obtained. The possibility of anti-inflammatory activation of metabolism in macrophages of different localization and ontogenetic origin obtained from old mice was demonstrated in vitro in coculture with thymic MMSC of young animals. In case of macrophages of monocytic origin, there was more profound effect of thymic MMSC on cells obtained from aged mice as compared to young. There was no age-dependence of MSC modulatory effect on macrophages of embryonic origin. Our results experimentally substantiate the feasibility of the use of MMSC cell therapy for anti-inflammatory metabolic polarization of tissue macrophages especially in aged persons. In addition, the protocol of neonatal tolerance induction to GFP-labeled caryocytes was developed. It can be used in the studies of cell migration and homing.