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Iron metabolism & its Disorders
Macrophage ferroportin is essential for stromal cell proliferation in wound healing
Stefania Recalcati,1# Elena Gammella,1# Paolo Buratti,1 Andrea Doni,2 Achille Anselmo,2 Massimo Locati2,3 and Gaetano Cairo1
1Department of Biomedical Sciences for Health, University of Milan; 2Humanitas Clinical and Research Center, Rozzano and 3Department of Medical Biotechnologies and Translational Medicine, University of Milan, Italy
ABSTRACT
Iron recycling by macrophages is essential for erythropoiesis, but may also be relevant for iron redistribution to neighboring cells at the local tissue level. Using mice with iron retention in macrophages due to tar- geted inactivation of the iron exporter ferroportin, we investigated the role of macrophage iron release in hair follicle cycling and wound heal- ing, a complex process leading to major clinical problems, if impaired. Genetic deletion of ferroportin in macrophages resulted in iron deficien- cy and decreased proliferation in epithelial cells, which consequently impaired hair follicle growth and caused transient alopecia. Hair loss was not related to systemic iron deficiency or anemia, thus indicating the necessity of local iron release from macrophages. Inactivation of macrophage ferroportin also led to delayed skin wound healing with defective granulation tissue formation and diminished fibroplasia. Iron retention in macrophages had no impact on the inflammatory processes accompanying wound healing, but affected stromal cell proliferation, blood and lymphatic vessel formation, and fibrogenesis. Our findings reveal that iron/ferroportin plays a largely underestimated role in macrophage trophic function in skin homeostasis and repair.
Introduction
Tissue resident macrophages play an important role both in tissue homeostasis, by supporting neighboring parenchymal cells with trophic signals and nutrients, and in tissue repair following injury.1-4 In the skin context, macrophages are critical regulators of hair follicle growth5 and cutaneous wound healing, two events with many similarities.6 Indeed, perifollicular macrophages prompt the entry of hair fol- licle stem cells into the anagen phase of growth,7 while selective ablation of macrophages impairs the wound healing response.8 Although wound macrophages display a mixed phenotypic and functional profile, the initial phase of an injury is characterized by the prevalence of pro-inflammatory, classically activated M1 macrophages, which are associated with the production of oxygen radicals and pro-inflammatory cytokines. Conversely, at later stages during reso- lution of inflammation and tissue repair, alternatively polarized M2 macrophages oriented to tissue repair and remodeling, predominate.1,9 This M1 to M2 switch is required for normal healing.2
Macrophages are also at the cross-road of iron traffic.10,11 Iron-recycling macrophages provide iron for erythropoiesis by clearing senescent erythrocytes.12 Conversely, iron sequestration by pro-inflammatory macrophages is a well- known mechanism of efficient bacteriostasis in host defense.13 In line with their different functions in homeostatic and inflammatory conditions, polarized macrophages show considerable differences in their transcriptional profiles,14 including a distinct regulation of genes related to iron metabolism.11,15 Iron reten- tion by M1 macrophages correlates with high expression of the iron storage pro- tein ferritin. Conversely, M2 macrophages display increased heme uptake and pro- duction of anti-inflammatory mediators via heme oxygenase-dependent heme
Ferrata Storti Foundation
Haematologica 2019 Volume 104(1):47-58
# SR and EG contributed equally to this work
Correspondence:
gaetano.cairo@unimi.it or massimo.locati@humanitasresearch.it or massimo.locati@unimi.it
Received: May 14, 2018. Accepted: August 14, 2018. Pre-published: August 16, 2018.
doi:10.3324/haematol.2018.197517
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/1/47
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