Published online before print July 2, 2009

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(American Journal of Pathology. 2009;175:547-556.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.081011

Macrophages Are Alternatively Activated in Patients with Endometriosis and Required for Growth and Vascularization of Lesions in a Mouse Model of Disease

Monica Bacci^*, Annalisa Capobianco^*, Antonella Monno^*, Lucia Cottone^*, Francesca Di Puppo, Barbara Camisa, Margherita Mariani, Chiara Brignole, Mirco Ponzoni, Stefano Ferrari, Paola Panina-Bordignon, Angelo A. Manfredi^* and Patrizia Rovere-Querini^*

From the Clinical Immunology and Innate Immunity and Tissue Remodelling Units,^* Division of Regenerative Medicine, Stem Cells, and Gene Therapy, and the Department of Gynaecology and Obstetrics, all from the H. San Raffaele Scientific Institute and Vita Salute San Raffaele University, Milano; Bioxell Spa, Milano; and the Laboratory of Oncology, G. Gaslini Children’s Hospital, Genova, Italy

The mechanisms that sustain endometrial tissues at ectopic sites in patients with endometriosis are poorly understood. Various leukocytes, including macrophages, infiltrate endometriotic lesions. In this study, we depleted mouse macrophages by means of either clodronate liposomes or monoclonal antibodies before the injection of syngeneic endometrial tissue. In the absence of macrophages, tissue fragments adhered and implanted into the peritoneal wall, but endometriotic lesions failed to organize and develop. When we depleted macrophages after the establishment of endometriotic lesions, blood vessels failed to reach the inner layers of the lesions, which stopped growing. Macrophages from patients with endometriosis and experimental mice, but not nonendometriotic patients who underwent surgery for uterine leiomyomas or control mice, expressed markers of alternative activation. These markers included high levels of scavenger receptors, CD163 and CD206, which are involved in both the scavenging of hemoglobin with iron transfer into macrophages and the silent clearance of inflammatory molecules. Macrophages in both inflammatory liquid and ectopic lesions were equally polarized, suggesting a critical role of environmental cues in the peritoneal cavity. Adoptively transferred, alternatively activated macrophages dramatically enhanced endometriotic lesion growth in mice. Inflammatory macrophages effectively protected mice from endometriosis. Therefore, endogenous macrophages involved in tissue remodeling appear as players in the natural history of endometriosis, required for effective vascularization and ectopic lesion growth.

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