Impact of individual intravenous iron preparations on the differentiation of monocytes towards macrophages and dendritic cells

Abstract

BackgroundTreatment of iron deficiency with intravenous (i.v.) iron is a first-line strategy to improve anaemia of chronic kidney disease. Previous in vitro experiments demonstrated that different i.v. iron preparations inhibit differentiation of haematopoietic stem cells to monocytes, but their effect on monocyte differentiation to macrophages and mature dendritic cells (mDCs) has not been assessed. We investigated substance-specific effects of iron sucrose (IS), sodium ferric gluconate (SFG), ferric carboxymaltose (FCM) and iron isomaltoside 1000 (IIM) on monocytic differentiation to M1/M2 macrophages and mDCs.MethodsVia flow cytometry and microRNA (miRNA) expression analysis, we morphologically and functionally characterized monocyte differentiation to M1/M2 macrophages and mDCs after monocyte stimulation with IS, SFG, FCM and IIM (0.133, 0.266 and 0.533 mg/mL, respectively). To assess potential clinical implications, we compared monocytic phagocytosis capacity in dialysis patients who received either 500 mg IS or IIM.ResultsPhenotypically, IS and SFG dysregulated the expression of macrophage (e.g. CD40, CD163) and mDC (e.g. CD1c, CD141) surface markers. Functionally, IS and SFG impaired macrophage phagocytosis capacity. Phenotypic and functional alterations were less pronounced with FCM, and virtually absent with IIM. In miRNA expression analysis of mDCs, IS dysregulated miRNAs such as miR-146b-5p and miR-155-5p, which are linked to Toll-like receptor and mitogen-activated protein kinase signalling pathways. In vivo, IS reduced monocytic phagocytosis capacity within 1 h after infusion, while IIM did not.ConclusionsThis study demonstrates that less stable i.v. iron preparations specifically affect monocyte differentiation towards macrophages and mDCs.

Safety of intravenous iron use in chronic kidney disease

“…The second and third-generation i.v. irons are considered equally efficacious in treating iron deficiency in equivalent doses but they differ in their stability [ 46 ], ability to induce oxidative stress [ 36 – 38 ], their effect on immune function [ 25 , 26 ], and dosing and administration options [ 47 ]. Iron isomaltoside seems to have a lower frequency of serious and severe hypersensitivity reactions, when using a novel approach of prospectively reported standardized medical terms pooled from different randomized trials.…”

“…irons having a potentially immunoactivating effect; for example, less stable i.v. irons, such as iron sucrose, induce phenotypical and functional monocytic alterations [ 25 ], and have a higher potential to modulate monocyte differentiation to macrophages and mature dendritic cells than more stable preparations [ 26 ]. A few small trials in CKD populations suggest an increased infection risk with i.v.…”

Neutrophil-derived extracellular vesicles: proinflammatory trails and anti-inflammatory microvesicles

“…miR-122-5p and miR-29a-3p induce proinflammatory gene expression in macrophages (Fabbri et al, 2012; Momen-Heravi et al, 2015). Moreover, miR-24-3p and miR-4454 are found in monocyte-derived dendritic cells (Fell et al, 2016) and alveolar macrophages (Armstrong et al, 2017). In contrast, miR-126-3p and miR-150-5p are expressed in M2 polarized macrophages (Cobos Jiménez et al, 2014; Escate et al, 2016) and are associated with suppression of inflammation (Harris et al, 2008; Lin et al, 2018; Manoharan et al, 2014; Shantikumar et al, 2012).…”

CD40/CD40L Signaling as a Promising Therapeutic Target for the Treatment of Renal Disease

“…In fact, CD40+ monocytes have been proposed as a biomarker indicating severity of CKD [81]. Iron preparations and iron salt have been shown to reduce the surface expression of CD40 in monocytes from CKD patients [82]. Additionally, the CD40+ intermediate monocyte subsets were negatively correlated with eGFR and positively correlated with plasma/cellular homocysteine [80].…”