Macrophages are mononuclear phagocytes. Most of them originate from the progenitor in the bone marrow [
19]. Once released from the blood vessels, macrophages migrate into the tissue associated with their differentiation into distinct population depending on the anatomical location and the microenvironment of the lesion. Each population of macrophage in specific tissue has a distinct functional profile and gene expression pattern [
20]. Different macrophage populations may also exhibit similar functions upon specific stimuli [
21], which indicate a remarkable plasticity of macrophages. As an important member of the immune system, macrophages express a wide range of phenotypes, from strong pro-inflammatory responses for elimination of pathogens to anti-inflammatory response for protection and tissue repair. In order to classify the different functions of macrophages, many studies tend to characterize the macrophages as classically or alternatively activated phenotypes based on their receptor composition, secretion profile, and response to the external stimuli [
22‐
24]. Classical activated phenotype, also called M1 macrophages, are activated by interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), or lipopolysaccharide (LPS) [
22,
23]. As a consequence, M1 macrophages could produce pro-inflammatory cytokines and chemokines participating in the early stage of injury, pro-inflammatory response, and myoblast proliferation [
25]. In contrast, alternatively activated macrophages or M2 macrophages are activated by IL-4, IL-10, IL-13, or transforming growth factor-β (TGF-β) [
26,
27]. Once activated, M2 macrophages secrete anti-inflammatory cytokines, growth factors, and other reparative factors [
25], which are involved in the anti-inflammatory response, an advanced stage of the repair and healing process. In short, M1 macrophages can kill tumor cells and clear pathogens by activating inflammatory or immune responses, whereas M2 macrophages are immunosuppressive cells that promote tissue repair, tumor angiogenesis, tumor growth, and tumor progression [
23].
As mentioned above, macrophages can exhibit high plasticity and different functional profiles. Thus, it is possible for the macrophage to be polarized toward a proper phenotype once stimulated by the signals triggered by the lesion. For example, tumor-associated macrophages (TuAMs) can polarize to M2 phenotype for tumor angiogenesis, growth, and metastasis [
28,
29]. With an opposite stimulus, TuAMs can also polarize toward M1 phenotype to exhibit inhibition of tumor growth and progression [
30,
31]. This discovery suggests that polarization of the macrophage is probably associated with pathogenesis and progression of the disease.
There have been many studies demonstrating the abnormal distribution of macrophages within the endometriotic lesion of patients with endometriosis [
13,
32,
33]. Macrophages in peritoneal fluid and endometriotic lesion can express markers of alternative activated phenotype, from both human specimens and mouse models [
34]. Human endometrial macrophages are predominantly M2 macrophages [
35]. The abnormal endometriotic milieu can induce the M2 polarization of macrophages leading to the development and invasiveness of endometrial stromal cells [
36]. In contrast, one research showed that the ratio of M2 macrophages was significantly lower in the endometriosis group, demonstrating that the macrophage population slants toward M1 in the endometrium of the endometriosis patient [
12]. The most likely reason for this discrepancy is the change of macrophage phenotype. In summary, the studies discussed above suggest a novel insight in the polarization of the macrophages in the progression of endometriosis.