Endometriosis, a disease of the macrophage

Abstract

Endometriosis, a common cause of pelvic pain and female infertility, depends on the growth of vascularized endometrial tissue at ectopic sites. Endometrial fragments reach the peritoneal cavity during the fertile years: local cues decide whether they yield endometriotic lesions. Macrophages are recruited at sites of hypoxia and tissue stress, where they clear cell debris and heme-iron and generate pro-life and pro-angiogenesis signals. Macrophages are abundant in endometriotic lesions, where are recruited and undergo alternative activation. In rodents macrophages are required for lesions to establish and to grow; bone marrow-derived Tie-2 expressing macrophages specifically contribute to lesions neovasculature, possibly because they concur to the recruitment of circulating endothelial progenitors, and sustain their survival and the integrity of the vessel wall. Macrophages sense cues (hypoxia, cell death, iron overload) in the lesions and react delivering signals to restore the local homeostasis: their action represents a necessary, non-redundant step in the natural history of the disease. Endometriosis may be due to a misperception of macrophages about ectopic endometrial tissue. They perceive it as a wound, they activate programs leading to ectopic cell survival and tissue vascularization. Clearing this misperception is a critical area for the development of novel medical treatments of endometriosis, an urgent and unmet medical need.

Keywords: Tie-2 expressing macrophages; alternatively activated macrophages; angiogenesis; endometriosis; hypoxia; iron; phagocytosis.

FIGURE 1

Macrophages come in different flavors. Microbial components such as lipopolysaccharide (LPS) and/or cytokines such as IFN-γ or GM-CSF elicit conventionally activated macrophages. These cells secrete inflammatory cytokines and generate molecules involved in the anti-bacterial response, such as reactive oxygen species (ROS). Treatment with different cytokines like IL-4 and/or IL-13, IL-10 and/or M-CSF supports the activation of alternative activated macrophages. Local hypoxia, possibly in conjunction with chemotactic signals such as CXCL12 and/or DAMPs, such as HMGB1, recruit from the blood precursors that yield Tie-expressing macrophages in the inflamed tissues. The expression of specific arrays of membrane receptors and the generation of soluble and gaseous messengers reflect the macrophage activation programs. LPS, lipopolysaccharide; IFN-γ, interferon-γ; GM-CSF, granulocyte macrophage-colony stimulating factor; M-CSF, macrophage-colony stimulating factor; MHCII, major histocompatibility complex class II; CD163, haptoglobin–hemoglobin complex receptor; CD206, mannose receptor; TGF-β, transforming growth factor β; PGE2, prostaglandin E2; ROS, reactive oxygen species.

FIGURE 2

Macrophages in experimental and human endometriosis. Endometrial fragments (maximal diameter <1 mm) derived from estradiol benzoate-treated mice (A) injected intra-peritoneally yield endometriotic lesions (B) that can be excised and processed for disease assessment (C) or immunohistochemical evaluation (D–G). CD68⁺ macrophages are abundant in human and experimental lesions (D,E). Most macrophages within human lesions express markers of alternative activation, such as the hemoglobin/haptoglobin CD163 scavenger receptor (F). CD163⁺ (green) vWF- (blue) pro-angiogenic Tie2-expressing macrophages surround the neoformed vessels (G).

FIGURE 3

Macrophages drive endometriosis. Endometrial cells reach the peritoneal cavity as a consequence of retrograde menstruation. The recruitment of macrophages at the site of endometrial cell engraftment is a limiting step for the lesion to organize and to growth. Local hypoxia and the production of chemokines play a major role in the recruitment of macrophages. Once endometriosis is established, the cyclic death of endometrial cells as a consequence of progesterone withdrawal leads to the release of cell debris, erythrocytes, and heme-bound iron in the peritoneal cavity. Recruited macrophages perceive ongoing cell death and tissue damage: in endometriotic patients they activate a reparative/regenerative/angiogenic program that is required for lesion maintenance, growth and spreading. In a subgroup of patients endometriosis is a preneoplastic condition. The persisting tissue healing action of macrophages that keep interfering with the physiological apoptosis while prompting proliferation of epithelial cells might set the scenario in which genetic alterations accumulate.