High Levels of Tumor Necrosis Factor-α Downregulate Antimicrobial Iron Transport Protein, Nramp1, in Chronic Hemodialysis Patients: A Key Factor for Infection Risk

Abstract

Background/Aims: The susceptibility of patients on maintenance hemodialysis (MHD) to infections is a major cause of mortality and morbidity. Natural resistance-associated macrophage protein 1 (Nramp1) regulates intracellular pathogen proliferation, and its mRNA expression is highest in polymorphonuclear leukocytes (PMNLs). The purpose of this study was to determine the level of Nramp1 in PMNLs from MHD patients and the factors affecting its expression. Methods: Twenty MHD patients and 24 healthy volunteers (controls) were recruited. Relative quantitative PCR was used to measure Nramp1 mRNA, and protein levels were semiquantified by means of real-time PCR and Western blot analysis or immunohistochemistry. The effect of tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6) on Nramp1 expression in PMNLs from controls was also examined. Results: Nramp1 mRNA and protein levels were substantially lower in PMNLs from MHD than control subjects. Serum TNF-α levels were significantly higher in the MHD group and were inversely correlated with Nramp1 mRNA levels. The addition of TNF-α to PMNLs from control subjects decreased mRNA and protein levels of Nramp1. IL-6 did not alter Nramp1 mRNA or protein expression. Conclusion: We found that Nramp1 was downregulated in the PMNLs of MHD patients, which constitute the first defense barrier against bacterial challenges. High levels of TNF-α may be associated with the downregulation of Nramp1. Our findings indicate that the susceptibility to infection observed in MHD patients could be partly due to the impairment of the intracellular handling of iron and the donation of more iron to the bacteria.

Down‐regulation of natural resistance‐associated macrophage protein‐1 (Nramp1) is associated with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)/1‐methyl‐4‐phenylpyridinium (MPP+)‐induced α‐synuclein accumulation and neurotoxicity

“…On the other hand, tumour necrosis factor-a (TNF-a) signalling in the dopaminergic neurones is found to be elevated in PD [43,44]. It is noted that Nramp1 expression is reported to be up-regulated by IFN-c [45], while down-regulated by TNF-a [46]. Thus, the inverse patterns of Nramp1 expression in the neurone and microglia may be attributed to cell-dependent response to cytokines.…”

Consumption of transgenic milk containing the antimicrobials lactoferrin and lysozyme separately and in conjunction by 6-week-old pigs improves intestinal and systemic health

“…The bone marrow has a constant need for iron to produce erythrocytes and leucocytes (Jacobs & Summers, 1981; Fonseca et al 2003; Drakesmith & Prentice, 2012). The main regulator of iron stores throughout the body is hepcidin and hepcidin expression is increased in certain tissues, such as macrophages, during inflammation (Moriguchi et al 2012; Wang et al 2012; Wu et al 2012). Lactoferrin, lysozyme, and many other antimicrobials and anti-inflammatory molecules also work by modulating the gut microbiota, promoting growth of beneficial bacteria like Bifidobacterium and Lactobacillus (Hu et al 2012; Maga et al 2012), which in turn lower the pH of the gut and discourage the growth of pathogenic bacteria (Ljungh & Wadström, 2006).…”

Iron Localization and Infectious Disease in Chronic Kidney Disease Patients

“…We have demonstrated that in dialysis patients without infection or malignancy, the iron level of PMNLs is increased and is associated with the downregulation of the iron export protein ferroportin (FPN) and upregulation of the iron import protein transferrin receptor (TfR). Additionally, the chemotactic peptide f-Met-Leu-Phe-stimulated degranulation activity of lactoferrin is also decreased [21,22] . Thus, human hosts with micro-inflammation, such as CKD patients, may use iron withholding as a form of nonspecific immunity to prevent infection in the presence of extracellular-residing microorganisms, even in the absence of infection.…”

“…M. tuberculosis growth and iron content were reduced in the macrophages from these patients compared with those from healthy adult volunteers [42] . As for the host defense, essential micronutrients, such as iron, are sequestered from intracellular M. tuberculosis by being exported from the phagosome by the divalent metal cation transporter natural resistance-associated macrophage protein 1 (Nramp1) [22,41,44] ( fig. 1 ).…”

“…It has been demonstrated that mutations in Nramp1 cause susceptibility to infection with the bacteria Salmonella and Mycobacteria and the protozoan Leishmania, which are classified as intracellular pathogens [45] . However, we demonstrated that the expression level of the phagosomal iron transport protein Nramp1 was significantly decreased in PMNLs from dialysis patients, and TNF-α caused a decline in the expression level of this protein in control PMNLs [13,22] . Thus, the iron storage pool in the phagosomes of infected macrophages may also favor the proliferation of Mycobacterium in CKD patients.…”