Polarization dictates iron handling by inflammatory and alternatively activated macrophages.
BACKGROUND
Macrophages play a key role in iron homeostasis. In peripheral tissues, they are known to polarize into classically activated (or M1) macrophages and alternatively activated (or M2) macrophages. Little is known on whether the polarization program influences the ability of macrophages to store or recycle iron and the molecular machinery involved in the processes.


METHODS
Inflammatory/M1 and alternatively activated/M2 macrophages were propagated in vitro from mouse bone-marrow precursors and polarized in the presence of recombinant interferon-γ or interleukin-4. We characterized and compared their ability to handle radioactive iron, the characteristics of the intracellular iron pools and the expression of molecules involved in internalization, storage and export of the metal. Moreover we verified the influence of iron on the relative ability of polarized macrophages to activate antigen-specific T cells.


RESULTS
M1 macrophages have low iron regulatory protein 1 and 2 binding activity, express high levels of ferritin H, low levels of transferrin receptor 1 and internalize--albeit with low efficiency -iron only when its extracellular concentration is high. In contrast, M2 macrophages have high iron regulatory protein binding activity, express low levels of ferritin H and high levels of transferrin receptor 1. M2 macrophages have a larger intracellular labile iron pool, effectively take up and spontaneously release iron at low concentrations and have limited storage ability. Iron export correlates with the expression of ferroportin, which is higher in M2 macrophages. M1 and M2 cells activate antigen-specific, MHC class II-restricted T cells. In the absence of the metal, only M1 macrophages are effective.


CONCLUSIONS
Cytokines that drive macrophage polarization ultimately control iron handling, leading to the differentiation of macrophages into a subset which has a relatively sealed intracellular iron content (M1) or into a subset endowed with the ability to recycle the metal (M2).
Corna
Gianfranca
G
H San Raffaele Institute, DIBIT-3A1, via Olgettina 58, 20132 Milano, Italy. rovere.patrizia@hsr.it.
Campana
Lara
L
Pignatti
Emanuele
E
Castiglioni
Alessandra
A
Tagliafico
Enrico
E
Bosurgi
Lidia
L
Campanella
Alessandro
A
Brunelli
Silvia
S
Manfredi
Angelo A
AA
Apostoli
Pietro
P
Silvestri
Laura
L
Camaschella
Clara
C
Rovere-Querini
Patrizia
P
D000818:Animals; D001052:Apoferritins / Q000096:biosynthesis / Q000276:immunology; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D007501:Iron / Q000276:immunology / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000096:biosynthesis / Q000276:immunology; D035942:Iron Regulatory Protein 2 / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D011990:Receptors, Transferrin / Q000096:biosynthesis / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D000098742:Ferroportin
D027682:Cation Transport Proteins; D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; D000098742:Ferroportin; D015847:Interleukin-4; D007371:Interferon-gamma; D001052:Apoferritins; D007501:Iron; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2