Abstract
Hyperglycemia, a hallmark of diabetes, can induce inflammatory programming of macrophages. The macrophage scavenger receptor CD163 internalizes and degrades hemoglobin-haptoglobin (Hb-Hp) complexes built due to intravascular hemolysis. Clinical studies have demonstrated a correlation between impaired scavenging of Hb-Hp complexes via CD163 and diabetic vascular complications. Our aim was to identify whether hyperglycemia is able to amplify inflammation via Hb-Hp complex interactions with the immune system. M(IFNγ), M(IL-4), and control M0 macrophages were differentiated out of primary human monocytes in normo- (5 mM) and hyperglycemic (25 mM) conditions. CD163 gene expression was decreased 5.53 times in M(IFNγ) with a further decrease of 1.99 times in hyperglycemia. Hyperglycemia suppressed CD163 surface expression in M(IFNγ) (1.43 times). Flow cytometry demonstrated no impairment of Hb-Hp uptake in hyperglycemia. However, hyperglycemia induced an inflammatory response of M(IFNγ) to Hb-Hp1-1 and Hb-Hp2-2 uptake with different dynamics. Hb-Hp1-1 uptake stimulated IL-6 release (3.03 times) after 6 h but suppressed secretion (5.78 times) after 24 h. Contrarily, Hb-Hp2-2 uptake did not affect IL-6 release after 6h but increased secretion after 24 h (3.06 times). Our data show that hyperglycemia induces an inflammatory response of innate immune cells to Hb-Hp1-1 and Hb-Hp2-2 uptake, converting the silent Hb-Hp complex clearance that prevents vascular damage into an inflammatory process, hereby increasing the susceptibility of diabetic patients to vascular complications.
Highlights
Diabetes mellitus is a heterogeneous group of metabolic disorders sharing the common ground of chronic hyperglycemia that induces micro- and macrovascular complications [1,2]
Hyperglycemia can induce an inflammatory program in innate immune cells on the epigenetic level, as we showed for the enhanced presence of activating histone marks on the promoters of S100A9 and S100A12 genes, responsible for vascular inflammation in diabetes [7,14,15,16]
We showed that hyperglycemia enhanced the proinflammatory response of M(IFNγ) to Hb-Hp complex uptake by stimulating the production of TNFα, IL-1β, IL-6, IL-8, and IL-1RA, supporting the observation that hyperglycemia itself can induce the secretion of proinflammatory cytokines [6]
Summary
Diabetes mellitus is a heterogeneous group of metabolic disorders sharing the common ground of chronic hyperglycemia that induces micro- and macrovascular complications [1,2]. Chronic inflammation is characterized by only moderate elevation of inflammatory cytokines, e.g., TNFα, IL-1β, and IL-6, induced by exogenous or endogenous factors [12]. The major source of inflammatory cytokines in chronic inflammation are macrophages. We have demonstrated previously that human macrophages respond to hyperglycemia by elevated production of predominantly proinflammatory cytokines [6,13]. Hyperglycemia can induce an inflammatory program in innate immune cells on the epigenetic level, as we showed for the enhanced presence of activating histone marks on the promoters of S100A9 and S100A12 genes, responsible for vascular inflammation in diabetes [7,14,15,16]. The effect of hyperglycemia on this essential function of monocytes and macrophages is unexplored
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