Cytokines in the mechanisms of regulation of monocytopoiesis in ischemic heart disease
Authors: Chumakova S. P. , Urazova O. I. , Denisenko O. A. , Vins M. V. , Shipulin V. M. , Pryakhin A. S. , Nevskaya K. V. , Gladkovskaya M. V. , Churina E. G. 
Published: December 2022

Introduction. The relationship of the violation of the subpopulation composition of blood monocytes in ischemic cardiomyopathy (ICMP) with changes in monocytopoiesis, as well as the effect of colony-stimulating factor of macrophages (M-CSF) and cytokines on the differentiation of monocytes of various immunophenotypes in the bone marrow is of great relevance.

Aim – to study the role of cytokines in the mechanisms of local and distant regulation of differentiation of classical, intermediate, non-classical and transitional bone marrow monocytes in combination with the content of VEGFR2+-monocytes and hypoxia-induced factor-1a (HIF-1a) in the blood of patients with ischemic heart disease (IHD), suffering and not suffering from ischemic cardiomyopathy.

Materials and methods. Seventy-four patients with IHD, suffering and not suffering from ICMP (30 and 44 people, respectively) were examined. The number of subpopulations of classical (CD14++CD16–), intermediate (CD14++CD16+), nonclassical (CD14+CD16++) and transitional (CD14+CD16–) monocytes (in bone marrow samples) and CD14+VEGFR2+-monocytes (in blood and bone marrow) was determined by flow cytofluorimetry; the concentration of cytokines IL-10, IL-13, TNF-α, IFN-γ, M-CSF in bone marrow and blood, as well as HIF-1a in the blood, was determined by ELISA.

Results. Content of hematopoietins IL-10, IL-13, TNF-α, M-CSF in the bone marrow, as well as the ability of M-CSF to activate and IL-13 to inhibit the differentiation of classical monocytes from transitional cell forms were comparable between groups of patients with IHD. In the blood of patients with ICMP the concentration of IL-10 was higher, and the content of HIF-1α and CD14+VEGFR2+-cells was lower than in patients with IHD without ICMP (IL-10 – 30.00 (26.25–34.50) pg/ mL vs. 0 (23.0–28.0) pg/mL, p < 0.05; HIF-1α – 0.040 (0.029–0.053) ng/mL vs. 0.063 (0.054–0.122) ng/mL, p < 0.05; CD14+VEGFR2+ – 7.00 (5.67–7.15) % vs. 7.80 (7.23–8.17) %, p < 0.05). A feature of monocytopoiesis in ICMP compared with patients with IHD without ICMP is a high concentration of IFN-γ in the BM and a low ratio of M-CSF/IL-13 (10.00 (0.65–18.23) and 0.02 [0–0.15) pg/mL, p < 0.001; 1.02 (0.41–2.00) and 9.00 (2.13–22.09), p < 0.05, respectively), in association with a decrease in the number of classical, intermediate monocytes and an increase in the number of transitional cells in the BM in patients with ICMP relative to patients without cardiomyopathy (21.0 (19.5–23.0) and 47 (41–61.5) %, p < 0.001; 0.3 (0.0–1.2) and 18.5 (6.5–28.0) %, p < 0.01; 76.2 (73.0–78.5) and 30.5 (13.0–41.5) %, p < 0.001, respectively). At the same time, regardless of the clinical form of IHD, IL-10 and IL-13 are distant hematopoietins, TNF-α is local hematopoietin.

Conclusion. An increase in the concentration of IFN-γ and a low ratio of M-CSF/IL-13 in the bone marrow, as well as an excess of IL-10 and a lack of HIF-1a and CD14+VEGFR2+-cells in the blood of IHD patients, are associated with inhibition of differentiation of mature forms of monocytes and the development of ICMP.