Endometriosis-Associated Macrophages: Origin, Phenotype, and Function

Abstract

Endometriosis is a complex, heterogeneous, chronic inflammatory condition impacting ~176 million women worldwide. It is associated with chronic pelvic pain, infertility, and fatigue, and has a substantial impact on health-related quality of life. Endometriosis is defined by the growth of endometrial-like tissue outside the uterus, typically on the lining of the pelvic cavity and ovaries (known as "lesions"). Macrophages are complex cells at the center of this enigmatic condition; they are critical for the growth, development, vascularization, and innervation of lesions as well as generation of pain symptoms. In health, tissue-resident macrophages are seeded during early embryonic life are vital for development and homeostasis of tissues. In the adult, under inflammatory challenge, monocytes are recruited from the blood and differentiate into macrophages in tissues where they fulfill functions, such as fighting infection and repairing wounds. The interplay between tissue-resident and recruited macrophages is now at the forefront of macrophage research due to their differential roles in inflammatory disorders. In some cancers, tumor-associated macrophages (TAMs) are comprised of tissue-resident macrophages and recruited inflammatory monocytes that differentiate into macrophages within the tumor. These macrophages of different origins play differential roles in disease progression. Herein, we review the complexities of macrophage dynamics in health and disease and explore the paradigm that under disease-modified conditions, macrophages that normally maintain homeostasis become modified such that they promote disease. We also interrogate the evidence to support the existence of multiple phenotypic populations and origins of macrophages in endometriosis and how this could be exploited for therapy.

Keywords: endometriosis; macrophage; monocyte; origin; phenotype.

Figure 1

Endometriosis is a chronic inflammatory condition. Endometriosis is characterized by the presence of endometrial-like tissue found outside the uterus, most commonly in the peritoneal cavity. Endometriosis lesions are heterogenous but usually contain endometrial stromal cells and epithelial glands, immune cell infiltrates and are vascularized and innervated by nerves. Created using Biorender.com.

Figure 2

Macrophages are mononuclear phagocytes. Tissue macrophages are seeded during fetal life from the fetal liver and yolk sack and undergo self-renewal. In adults, monocyte precursors extravasate from the bone marrow into the circulation, where they can then infiltrate into tissues and differentiate into macrophages. In tissues, macrophages modulate their phenotype dependent on local cytokines and growth factors to specific tissue or disease-associated phenotypes.

Figure 3

Endometriosis lesions are infiltrated by blood vessels, nerves, and macrophages. Lesion resident macrophages are derived from macrophages originating from the endometrium and recruited macrophages. Macrophages interact with blood vessels and nerves to stimulate their growth. Signaling also occurs between macrophages and stromal cells, which increases their clonal expansion and invasive properties. Created using Biorender.com.