Monocytes and cells of the dendritic cell lineage circulate in blood and eventually migrate into tissue where they further mature and serve various functions, most notably in immune defense. Over recent years these cells have been characterized in detail with the use of cell surface markers and flow cytometry, and subpopulations have been described. The present document proposes a nomenclature for these cells and defines 3 types of monocytes (classical, intermediate, and nonclassical monocytes) and 3 types of dendritic cells (plasmacytoid and 2 types of myeloid dendritic cells) in human and in mouse blood. This classification has been approved by the Nomenclature Committee of the International Union of Immunological Societies, and we are convinced that it will facilitate communication among experts and in the wider scientific community.
The high cardiovascular morbidity and mortality of patients with CKD may result in large part from medial vascular calcification, a process promoted by hyperphosphatemia and involving osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Reduced serum zinc levels have frequently been observed in patients with CKD, but the functional relevance of this remains unclear. We performed experiments in primary human aortic VSMCs; klotho-hypomorphic (), subtotal nephrectomy, and cholecalciferol-overload mouse calcification models; and serum samples from patients with CKD. In cultured VSMCs, treatment with zinc sulfate (ZnSO) blunted phosphate-induced calcification, osteo-/chondrogenic signaling, and NF-B activation. ZnSO increased the abundance of zinc-finger protein TNF--induced protein 3 (TNFAIP3, also known as A20), a suppressor of the NF-B pathway, by zinc-sensing receptor ZnR/GPR39-dependent upregulation of gene expression. Silencing of TNFAIP3 in VSMCs blunted the anticalcific effects of ZnSO under high phosphate conditions. mice showed reduced plasma zinc levels, and ZnSO supplementation strongly blunted vascular calcification and aortic osteoinduction and upregulated aortic Tnfaip3 expression. ZnSO ameliorated vascular calcification in mice with chronic renal failure and mice with cholecalciferol overload. In patients with CKD, serum zinc concentrations inversely correlated with serum calcification propensity. Finally, ZnSO ameliorated the osteoinductive effects of uremic serum in VSMCs. Zinc supplementation ameliorates phosphate-induced osteo-/chondrogenic transdifferentiation of VSMCs and vascular calcification through an active cellular mechanism resulting from GPR39-dependent induction of TNFAIP3 and subsequent suppression of the NF-B pathway. Zinc supplementation may be a simple treatment to reduce the burden of vascular calcification in CKD.
The majority of peripheral blood monocytes strongly positive for the lipopolysaccharides (LPS)-receptor CD14 are negative for Fcgamma receptor type III (CD16). However, a subset of monocytes coexpressing CD14 and CD16 accounts for about 8% of all monocytes. This population exhibits features of tissue macrophages, and is largely expanded (> 20%) during acute and chronic inflammatory diseases including cases with pararheumatic systemic vasculitis. In addition, compared to normal controls, soluble CD14 (sCD14) is elevated (> 3 microg/ml) in serum specimens of these patients. CD14+/CD16+ monocytes show a higher phagocytosis rate than CD14+/CD16 negative cells, and express higher levels of interleukin-1 and major histocompatibility complex, such as histocompatibility antigens HLA-DR, -DP and -DQ antigens. Glucocorticoids downregulate expression of CD14 and rapidly deplete CD14+/CD16+ monocytes from peripheral blood. Patients under chronic immunosuppressive therapy exhibit low CD14/+/CD16+ rates, which may rise during infectious and non-infectious inflammatory complications, however. Thus, serial analyses for sCD14 and the proinflammatory CD14+/CD16+ subset of monocytes suggest a valuable tool monitoring patients under immunosuppressive and/or antiinflammatory therapy.
Aims Uromodulin is produced exclusively in the kidney and secreted into both urine and blood. Serum levels of uromodulin are correlated with kidney function and reduced in chronic kidney disease (CKD) patients, but physiological functions of serum uromodulin are still elusive. This study investigated the role of uromodulin in medial vascular calcification, a key factor associated with cardiovascular events and mortality in CKD patients. Methods and results Experiments were performed in primary human (HAoSMCs) and mouse (MOVAS) aortic smooth muscle cells, cholecalciferol overload and subtotal nephrectomy mouse models and serum from CKD patients. In three independent cohorts of CKD patients, serum uromodulin concentrations were inversely correlated with serum calcification propensity. Uromodulin supplementation reduced phosphate-induced osteo-/chondrogenic transdifferentiation and calcification of HAoSMCs. In human serum, pro-inflammatory cytokines tumour necrosis factor α (TNFα) and interleukin-1β (IL-1β) co-immunoprecipitated with uromodulin. Uromodulin inhibited TNFα and IL-1β-induced osteo-/chondrogenic signalling and activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated β cells (NF-kB) as well as phosphate-induced NF-kB-dependent transcriptional activity in HAoSMCs. In vivo, adeno-associated virus (AAV)-mediated overexpression of uromodulin ameliorated vascular calcification in mice with cholecalciferol overload. Conversely, cholecalciferol overload-induced vascular calcification was aggravated in uromodulin-deficient mice. In contrast, uromodulin overexpression failed to reduce vascular calcification during renal failure in mice. Carbamylated uromodulin was detected in serum of CKD patients and uromodulin carbamylation inhibited its anti-calcific properties in vitro. Conclusions Uromodulin counteracts vascular osteo-/chondrogenic transdifferentiation and calcification, at least in part, through interference with cytokine-dependent pro-calcific signalling. In CKD, reduction and carbamylation of uromodulin may contribute to vascular pathology.
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