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Anemia of Inflammation : IL-6 Induced Anemia - By Activation Of Hepcidin Which Blocks Iron Uptake. Cobalt (High Serum B12), and Aluminum Effect Iron Homeostasis And Induce High Free UnBound Iron And

This article is not medical advice. Before starting on any health related regimen, seek the advice of your Primary Care Physician, or an M.D.


The title says it all pretty much. IL-6 - one of the most chronically elevated markers in inflammation, be it mold, Long Haul, CFS, etc - is directly linked to Hepcidin levels which inhibits iron absorption through the intestinal wall, but also prevents iron from exiting the cell through ferroportin, which can lead to high intracellular iron and thus high intracellular inflammation.


"The effects of IL-6 on erythropoiesis likely include iron-mediated and iron-independent actions. IL-6 is the major upstream activator of hepcidin, a hepatic iron-regulatory hormone, in anemia of inflammation.24, 25, 26 Hepcidin binds to iron exporter ferroportin, expressed on enterocytes, hepatocytes, and macrophages, forming a hepcidin-ferroportin complex that is internalized to undergo lysosomal degradation, which prevents iron egress from the cells. Thus, increased hepcidin, due to higher circulating levels of IL-6, leads to iron sequestration, decreased iron absorption, and lack of iron availability for erythropoiesis. Because iron availability is a rate-limiting step in the maturation of RBCs, hepcidin overproduction leads to anemia."


"Anemia of inflammation (AI), previously known as anemia of chronic diseases, is a moderate normochromic-normocytic anemia that develops in conditions of systemic inflammation and immune activation. It occurs in several common disorders, including chronic infections, autoimmune diseases, advanced cancer, chronic kidney disease, congestive heart failure, chronic obstructive pulmonary disease, anemia of the elderly (at least partly), and graft versus host disease. AI is one of the most common anemias worldwide and the most frequent anemia in hospitalized patients. Acute inflammation contributes to the severity of anemia in intensive care units. Molecular mechanisms underlying AI are multiple and complex. Overproduction of cytokines such as IL1-β, TNF-α, and IL-6 by macrophages and INF-γ by lymphocytes blunts EPO production, impairs the erythropoiesis response, increases hepcidin levels, and may activate erythrophagocytosis, especially in the acute forms (Weiss and Goodnough, 2005; Ganz, 2019).

Hepcidin is activated by IL-6 through IL-6 receptor (IL-6R) and JAK2-STAT3 signaling. Full hepcidin activation requires an active BMP-SMAD pathway because inactivation of BMP signaling decreases hepcidin in animal models of inflammation (Theurl et al., 2011). The deregulation of systemic iron homeostasis causes macrophage iron sequestration and reduced absorption and recycling that leads to low saturation of transferrin and iron restriction of erythropoiesis and other tissues."[2]


"Relatively little is known about how metals such as iron are effluxed from cells, a necessary step for transport from the root to the shoot. Ferroportin (FPN) is the sole iron efflux transporter identified to date in animals, and there are two closely related orthologs in Arabidopsis thaliana, IRON REGULATED1 (IREG1/FPN1) and IREG2/FPN2. FPN1 localizes to the plasma membrane and is expressed in the stele, suggesting a role in vascular loading; FPN2 localizes to the vacuole and is expressed in the two outermost layers of the root in response to iron deficiency, suggesting a role in buffering metal influx. Consistent with these roles, fpn2 has a diminished iron deficiency response, whereas fpn1 fpn2 has an elevated iron deficiency response. Ferroportins also play a role in cobalt homeostasis; a survey of Arabidopsis accessions for ionomic phenotypes showed that truncation of FPN2 results in elevated shoot cobalt levels and leads to increased sensitivity to the metal. Conversely, loss of FPN1 abolishes shoot cobalt accumulation, even in the cobalt accumulating mutant frd3. Consequently, in the fpn1 fpn2 double mutant, cobalt cannot move to the shoot via FPN1 and is not sequestered in the root vacuoles via FPN2; instead, cobalt likely accumulates in the root cytoplasm causing fpn1 fpn2 to be even more sensitive to cobalt than fpn2 mutants."[3]


"Aluminum and other trivalent metals were shown to stimulate uptake of transferrin bound iron and nontransferrin bound iron in erytholeukemia and hepatoma cells. Because of the association between aluminum and Alzheimer’s Disease, and findings of higher levels of iron in Alzheimer’s disease brains, the effects of aluminum on iron homeostasis were examined in a human glial cell line. Aluminum stimulated dose- and time-dependent uptake of nontransferrin bound iron and iron bound to transferrin. A transporter was likely involved in the uptake of nontransferrin iron because uptake reached saturation, was temperature-dependent, and attenuated by inhibitors of protein synthesis. Interestingly, the effects of aluminum were not blocked by inhibitors of RNA synthesis. Aluminum also decreased the amount of iron bound to ferritin though it did not affect levels of divalent metal transporter 1. These results suggest that aluminum disrupts iron homeostasis in the brain by several mechanisms including the transferrin receptor, a nontransferrin iron transporter, and ferritin."[5]


"Balancing systemic iron levels within narrow limits is critical for maintaining human health. There are no known pathways to eliminate excess iron from the body and therefore iron homeostasis is maintained by modifying dietary absorption so that it matches daily obligatory losses. Several dietary factors can modify iron absorption. Polyphenols are plentiful in human diet and many compounds, including quercetin – the most abundant dietary polyphenol – are potent iron chelators. The aim of this study was to investigate the acute and longer-term effects of quercetin on intestinal iron metabolism. Acute exposure of rat duodenal mucosa to quercetin increased apical iron uptake but decreased subsequent basolateral iron efflux into the circulation. Quercetin binds iron between its 3-hydroxyl and 4-carbonyl groups and methylation of the 3-hydroxyl group negated both the increase in apical uptake and the inhibition of basolateral iron release, suggesting that the acute effects of quercetin on iron transport were due to iron chelation. In longer-term studies, rats were administered quercetin by a single gavage and iron transporter expression measured 18 h later. Duodenal FPN expression was decreased in quercetin-treated rats. This effect was recapitulated in Caco-2 cells exposed to quercetin for 18 h. Reporter assays in Caco-2 cells indicated that repression of FPN by quercetin was not a transcriptional event but might be mediated by miRNA interaction with the FPN 3′UTR. Our study highlights a novel mechanism for the regulation of iron bioavailability by dietary polyphenols. Potentially, diets rich in polyphenols might be beneficial for patients groups at risk of iron loading by limiting the rate of intestinal iron absorption."[6]


"Haptoglobin is an acute phase protein responsible for the recovery of free hemoglobin from plasma. Haptoglobin-null mice were previously shown to have an altered heme-iron distribution, thus reproducing what occurs in humans in cases of congenital or acquired anhaptoglobinemia. Here, we report the analysis of iron homeostasis in haptoglobin-null mice. Methods: Iron absorption was measured in tied-off duodenal segments. Iron stores were evaluated on tissue homogenates and sections. The expression of molecules involved in iron homeostasis was analyzed at the protein and messenger RNA levels both in mice and in murine RAW264.7 macrophages stimulated in vitro with hemoglobin. Results: Analysis of intestinal iron transport reveals that haptoglobin-null mice export significantly more iron from the duodenal mucosa to plasma compared with control counterparts. Increased iron export from the duodenum correlates with increased duodenal expression of ferroportin, both at the protein and messenger RNA levels, whereas hepatic hepcidin expression remains unchanged. Up-regulation of the ferroportin transcript, but not of the protein, also occurs in haptoglobin-null spleen macrophages, which accumulate free hemoglobin-derived iron. Finally, we demonstrate that hemoglobin induces ferroportin expression in RAW264.7 cells. Conclusions: Taking together these data, we suggest that haptoglobin, by controlling plasma levels of hemoglobin, participates in the regulation of ferroportin expression, thus contributing to the regulation of iron transfer from duodenal mucosa to plasma."[7]


"Aluminum toxicity is well documented but the mechanism of action is poorly understood. In renal failure patients with aluminum overload, disturbances in iron metabolism leading to anemia are apparent. Few animal models, however, have been used to study the effects of dietary aluminum on iron metabolism. The purpose of this study was to determine if dietary aluminum exposure alters tissue iron and ferritin concentrations in the chick, as has been found in cultured human cells exposed to aluminum. Groups of day-old chicks were fed purified diets containing one of two levels of iron (control or high iron), and one of three levels of aluminum chloride in a 2 x 3 factorial design. Diets were consumed ad libitum for 1 week, then pair-feeding was initiated for 2 more weeks. A seventh group consumed a low iron diet ad libitum for comparative purposes. After the 3-week feeding period, samples of kidney, liver, and intestinal mucosa were analyzed for nonheme iron and ferritin concentrations by a colorimetric assay and SDS-PAGE, respectively. Results showed that dietary aluminum intake reduced iron stores in liver and intestine, but had no effect on nonheme iron levels in the kidney. Ferritin levels were reduced by aluminum intake in all tissues studied. The decreases in tissue ferritin levels were proportionately more than the decreases in tissue nonheme iron levels. This resulted in increased nonheme iron to ferritin ratios that amounted to as much as 140 and 525% in kidney and intestine, respectively. These findings are consistent with the interpretation that, in the growing chick, dietary aluminum can inhibit iron absorption, disrupt the regulation of tissue ferritin levels by iron, and potentially alter the compartmentalization and protective sequestration of iron within cells.[8]


"Aluminum (Al), a known environmental toxicant, has been linked to a variety of pathological conditions such as dialysis dementia, osteomalacia, Alzheimer's disease, and Parkinson's disease. However, its precise role in the pathogenesis of these disorders is not fully understood. Using hepatocytes as a model system, we have probed the impact of this trivalent metal on the aerobic energy-generating machinery. Here we show that Al-exposed hepatocytes were characterized by lipid and protein oxidation and a dysfunctional tricarboxylic acid (TCA) cycle. BN-PAGE, SDS-PAGE, and Western blot analyses revealed a marked decrease in activity and expression of succinate dehydrogenase (SDH), alpha-ketoglutarate dehydrogenase (KGDH), isocitrate dehydrogenase-NAD+ (IDH), fumarase (FUM), aconitase (ACN), and cytochrome c oxidase (Cyt C Ox). 13C-NMR and HPLC studies further confirmed the disparate metabolism operative in control and Al-stressed cells and provided evidence for the accumulation of succinate in the latter cultures. In conclusion, these results suggest that Al toxicity promotes a dysfunctional TCA cycle and impedes ATP production, events that may contribute to various Al-induced abnormalities."[10]


References:

  1. Interleukin-6 Contributes to the Development of Anemia in Juvenile CKD. Kidney Int Rep. 2019 Mar; 4(3): 470–483. By Akchurn, et. al. Published online 2018 Dec 19. doi: 10.1016/j.ekir.2018.12.006. PMCID: PMC6409399. PMID: 30899874

  2. Hepcidin and Anemia: A Tight Relationship. By Alessia Pagani. Front. Physiol., 08 October 2019. Sec. Red Blood Cell Physiology. Volume 10 - 2019 | https://doi.org/10.3389/fphys.2019.01294

  3. The Ferroportin Metal Efflux Proteins Function in Iron and Cobalt Homeostasis in Arabidopsis. By Joe Morrissey, et. al. The Plant Cell, Volume 21, Issue 10, October 2009, Pages 3326–3338, https://doi.org/10.1105/tpc.109.069401 Published: 27 October 2009

  4. Effect Of Dietary Aluminum on Iron and Ferritin Metabolism. By Wu. Thesis for Masters Of Science In Nutritional Sciences 2004.

  5. ALUMINUM STIMULATES UPTAKE OF NON-TRANSFERRIN BOUND IRON AND TRANSFERRIN BOUND IRON IN HUMAN GLIAL CELLS. By Kim, et. al. Toxicol Appl Pharmacol. Author manuscript; available in PMC 2011 May 19. Toxicol Appl Pharmacol. 2007 May 1; 220(3): 349–356. Published online 2007 Feb 9. doi: 10.1016/j.taap.2007.02.001 PMCID: PMC3097386. NIHMSID: NIHMS22933. PMID: 17376497

  6. Quercetin Inhibits Intestinal Iron Absorption and Ferroportin Transporter Expression In Vivo and In Vitro. By Marija Lesjak. Published: July 24, 2014. https://doi.org/10.1371/journal.pone.0102900

  7. Lack of Haptoglobin Affects Iron Transport Across Duodenum by Modulating Ferroportin Expression. By Samuele Marro, et. al. Published:July 12, 2007DOI:https://doi.org/10.1053/j.gastro.2007.07.004. BASIC–ALIMENTARY TRACT| VOLUME 133, ISSUE 4.

  8. Effect of dietary aluminum on tissue nonheme iron and ferritin levels in the chick J Han, et. al. Toxicology. . 2000 Jan 3;142(2):97-109. doi: 10.1016/s0300-483x(99)00119-5. PMID: 10685509. DOI: 10.1016/s0300-483x(99)00119-5

  9. Aluminium toxicosis: a review of toxic actions and effects. By Ikechukwu Onyebuchi Igbokwe, Ephraim Igwenagu, and Nanacha Afifi Igbokwe. Interdiscip Toxicol. 2019 Oct; 12(2): 45–70. Published online 2020 Feb 20. doi: 10.2478/intox-2019-0007 PMCID: PMC7071840. PMID: 32206026

  10. Aluminum toxicity elicits a dysfunctional TCA cycle and succinate accumulation in hepatocytes. By Ryan J Mailloux, J Biochem Mol Toxicol. . 2006;20(4):198-208. doi: 10.1002/jbt.20137. PMID: 16906525. DOI: 10.1002/jbt.20137

  11. Mechanism of aluminum-induced inhibition of hepatic glycolysis: inactivation of phosphofructokinase. By Z X Xu. J Pharmacol Exp Ther. . 1990 Jul;254(1):301-5. PMID: 2142221.



  1. , P1261-1271.E3, OCTOBER 200



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