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.

Leukocytes recruited by tumor-derived HMGB1 sustain peritoneal carcinomatosis

“…15,22 In the latter condition, macrophages deliver signals that contribute to the attraction of neo-vessels, possibly facilitating the survival of ectopic endometrial cells in the peritoneal cavity, a relatively hypoxic environment. 23 A license from macrophages could as well be required when cancer cells derived from abdominal organs adhere to the serosal lining. If this were the case, one would expect that only a minority of exfoliated tumor cells yield lesions.…”

Estradiol Is a Critical Mediator of Macrophage-Nerve Cross Talk in Peritoneal Endometriosis

“…39 Macrophages are vital in the regeneration of damaged nerves after injury to the central nervous system and peripheral nervous system and, although infiltrating sensory nerves present within endometriosis lesions are not damaged per se, they may experience a chemical milieu similar to inflammation in response to trauma. 40 In a mouse model of acute peripheral nerve injury, an alternative macrophage response was detected, 41 and this phenotype has been associated with a sterile inflammatory environment similar to endometriosis.…”

Role of iron overload-induced macrophage apoptosis in the pathogenesis of peritoneal endometriosis

“…By contrast, immunosuppressive M2 macrophages resolve inflammation and promote parasite killing, angiogenesis, wound healing, matrix remodeling, and tumor growth by increasing the availability of extracellular iron and polarized Th2 responses (Brunelli & Rovere-Querini 2008, Corna et al 2010, Gaetano et al 2010, Recalcati et al 2010 The inflammatory peritoneal environment characterizes macrophage polarization toward the M2 phenotype expressing markers of alternative activation, particularly high levels of scavenger receptors, CD163 and CD206, which are involved in the export of hemederived iron and removal of inflammatory mediators respectively (Smith et al 2012, Capobianco & RovereQuerini 2013. Impaired ability of peritoneal macrophages to dispose apoptotic endometrial remnants and defective scavenging heme-bound iron, resulting from cyclic progesterone withdrawal, may activate macrophages recruited at sites of local hypoxia and tissue stress (Capobianco & Rovere-Querini 2013). The activation of peritoneal macrophages by the environmental cues such as local hypoxia and iron overload may provide a permissive environment to vascularization and growth of ectopic endometriosis lesions via reduced immune clearance of endometrial cells (Bacci et al 2009).…”