Estrogen receptor-alpha promotes alternative macrophage activation during cutaneous repair.
Efficient local monocyte/macrophage recruitment is critical for tissue repair. Recruited macrophages are polarized toward classical (proinflammatory) or alternative (prohealing) activation in response to cytokines, with tight temporal regulation crucial for efficient wound repair. Estrogen acts as a potent anti-inflammatory regulator of cutaneous healing. However, an understanding of estrogen/estrogen receptor (ER) contribution to macrophage polarization and subsequent local effects on wound healing is lacking. Here we identify, to our knowledge previously unreported, a role whereby estrogen receptor α (ERα) signaling preferentially polarizes macrophages from a range of sources to an alternative phenotype. Cell-specific ER ablation studies confirm an in vivo role for inflammatory cell ERα, but not ERβ, in poor healing associated with an altered cytokine profile and fewer alternatively activated macrophages. Furthermore, we reveal intrinsic changes in ERα-deficient macrophages, which are unable to respond to alternative activation signals in vitro. Collectively, our data reveal that inflammatory cell-expressed ERα promotes alternative macrophage polarization, which is beneficial for timely healing. Given the diverse physiological roles of ERs, these findings will likely be of relevance to many pathologies involving excessive inflammation.
The Healing Foundation Centre, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
Laura
L
Campbell
The Healing Foundation Centre, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
Elaine
E
Emmerson
The Healing Foundation Centre, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
Helen
H
Williams
The Healing Foundation Centre, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
Charis R
CR
Saville
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Collège de France, Paris, France.
Andrée
A
Krust
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Collège de France, Paris, France.
Pierre
P
Chambon
The Healing Foundation Centre, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
Kimberly A
KA
Mace
The Healing Foundation Centre, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom. Electronic address: matthew.j.hardman@manchester.ac.uk.
Matthew J
MJ
Hardman
D000818:Animals; D047628:Estrogen Receptor alpha / Q000276:immunology* / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000276:immunology / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010052:Ovariectomy; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D014945:Wound Healing / Q000276:immunology*
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse