Influence of soluble factors from the M2 phenotype macrophages on hematopoiesis in depression-like state

Abstract

Chronic psychosocial stress provokes anxious behavior and depressive disorders. The longitudinal stress-induced neuroendocrine signals may alter functioning of immune (central and peripheral) organs. Increased myelopoiesis is observed in bone marrow, being detrimental to lympho- and erythropoiesis, with increased emigration of monocytic bone marrow cells to the periphery and their acquisition of “inflammatory” phenotype. The subsequent migration of such monocytes to the brain with differentiation into the M1 type macrophages which form inflammatory signals, and their effect upon endothelial cells and microglia leads to increased production of cytokines, chemokines, and adhesion molecules, thus accelerating accumulation of bone marrow-derived monocytes migrating to the brain. The signals from bone marrow monocytes and activated microglia promote neuroinflammatory condition which leads to behavioral changes. Current data on the presence of non-resident bone marrow macrophages in the brain of depressed patients require studies of hematopoiesis in depression-like states. Pronounced plasticity is a characteristic feature of macrophages, i.e., their ability to acquire M1 or M2 phenotype depending on the microenvironment signals. M1 exhibit high pro-inflammatory activity and have neurodestructive properties, whereas M2 cells are characterized by low pro-inflammatory activity and pronounced regenerative potential, due to the production of multiple soluble mediators and cytokines, including neurotrophic and immunoregulatory factors, anti-inflammatory substances that provide neuroprotection, stimulate neurogenesis, synaptogenesis, growth and myelinization of axons, thus theoretically substantiating an opportunity of using the potential of M2 macrophages in the treatment of depression. In this work, we studied the effect of soluble factors of human macrophages, polarized into cells with M2 phenotype under the conditions of serum deprivation, upon bone marrow hematopoiesis and peripheral blood cells in a model of stress-induced depression. We have shown enhanced differentiation of hematopoietic stem cells into the granulocyte-macrophage (CFU-GM) lineage, along with increased monocyte population in peripheral blood in the depressive-like murine model. Development of a depressive-like state in the animals was associated with reduced amounts of both erythroid precursors in bone marrow and erythrocytes/hemoglobin in peripheral blood. Intranasal administration of soluble M2 macrophage factors (M2-SFs) for 7 days was accompanied by a corrective effect on the above parameters, being significant for peripheral blood monocytes. The data obtained suggest effectiveness of the M2-SFS anti-inflammatory effects in correcting changes in hematopoiesis caused by social stress in depressive-like animals.