Accordingly, a strong body of evidence implicates a prominent role for alveolar macrophages as drivers of chronic inflammation in COPD. that genes for heme metabolism are related to lifespan and healthspan  and indicating that higher systemic iron status may reduce life expectancy . The control of iron balance is particularly crucial in the context of contamination/inflammation, in which pathogens use multiple mechanisms to acquire iron, whereas the host sequesters iron and starves them of this essential metal. The universality of this response is usually highlighted by the appreciation that this competition for iron occurs also in plants, as iron sequestration is usually important for herb immune responses . Macrophages, which handle a large proportion of the daily iron turnover, play a key role in the regulation of iron availability in mammals . Macrophages seem to withstand iron with less damage than other cells, possibly because in response to heme loading they are able to reprogram their bioenergetic metabolism by decreasing oxidative phosphorylation and shifting to the pentose phosphate pathway that provides NADPH . This mechanism decreases mitochondrial ROS production and, at the same time, NADPH facilitates the maintenance of redox homeostasis, e.g., by functioning as cofactor of the antioxidant protein heme oxygenase 1. Another pathway involved in heme tolerance may be represented by a mechanism leading to crystallization of extra heme into hemozoin. In fact, it has been shown that macrophages lacking the heme exporter HRG1 retain high levels of heme into erythrophagosomes; however, they tolerate this heme burden by forming hemozoin biocrystals, which is the same detoxification stratagem used by blood-feeding parasites to avoid heme toxicity . 2. Control of Iron Homeostasis Since iron is usually a double-edged sword, sophisticated mechanisms have developed to maintain iron sense of balance both at the systemic and cellular levels. Cellular iron homeostasis is usually regulated through multiple control mechanisms, but the iron regulatory proteins (IRP)-dependent post-translational regulation, which controls the expression of proteins involved in iron uptake (transferrin receptor, TfR1 and DMT1), storage (H and L ferritin subunits), release (ferroportin (FPN)) and utilization (e.g., eALAS), is probably the most relevant . Body iron is mainly regulated by the hepcidin/FPN axis ; hepcidin is usually a liver-derived peptide that exerts its function by controlling the presence around the cell surface of FPN, which could be considered the sole cellular iron exporter, although it has been recently shown that prominin2 promotes the formation of ferritin-containing multivesicular body and exosomes that transport iron out of the cell, thereby facilitating ferroptosis resistance . Hepcidin binding inhibits iron release by triggering FPN internalization and degradation  and occluding its cavity . As such, the hepcidin/FPN axis is the main regulator of intestinal iron uptake from dietary sources and iron release by splenic and hepatic macrophages involved in iron recycling from reddish blood cell TMSB4X breakdown . Interestingly, GSK2838232 an additional source of iron for the blood circulation has been explained: erythroblasts also, despite their high iron consumption, return iron to the blood circulation through FPN (transcribed from the alternative mRNA not subject to IRP control) and significantly contribute to serum iron levels . In these erythroid precursors, FPN is usually highly expressed and exports the iron presumably made available by both TfR1-mediated uptake and heme degradation; the latter could be catalyzed by heme oxygenase, which is usually expressed in erythroblasts , and/or derived by hemoglobin auto-oxidation . Disruption in these regulatory mechanisms results in a variety of disorders associated with iron deficiency or overload. Notably, iron GSK2838232 deficiency anemia, which affects two billion people worldwide, represents GSK2838232 the most common nutritional disorder. FPN seems to be localized in a strategic position at the crossroads of these pathways. Over recent years, increasing evidence has emerged to indicate that, in addition to its role in systemic iron metabolism, FPN may play an important function in local iron control, such that its dysregulation may lead to tissue damage despite unaltered systemic iron homeostasis. In this review, we discuss the importance of local iron availability in the microenvironment as an essential factor to maintain tissue homeostasis or repair. Particular attention is usually paid to iron recycling by macrophages, which is essential for erythropoiesis and may also be relevant for iron redistribution to neighboring cells at the local tissue level . 3. Ferroportin FPN (SLC40A1), a member of the large solute carrier gene family, is usually a.