EM is a chronic gynecological disorder characterized by the presence and growth of endometrial-like tissue outside the uterus, referred to as ectopic lesions. Despite its global impact on approximately 200 million individuals and the profound reduction in their quality of life, the exact origins of EM remain elusive (Giudice and Kao, 2004). Accumulating evidence, including our previous studies, highlights that components of the ECS are dysregulated within the EM lesion microenvironment as well as in the systemic circulation of EM patients (Lingegowda et al., 2021b; Bilgic et al., 2017; Shen et al., 2019). The ECS is a complex signaling network comprised of canonical receptors (CNR1 and CNR2) and endocannabinoid (EC) ligands, along with a non-canonical extended signaling network of ligands and enzymes extensively reviewed elsewhere (Di Marzo et al., 2004). CNR1 and CNR2 are primarily expressed in nerve tissues, immune cells, and reproductive tissues, where they regulate various physiological processes, including pain perception, immune responses, and reproductive functions (Zou and Kumar, 2018). Consequently, EM pathogenesis has been postulated as a consequence of EC deficiency (Russo, 2016; Lingegowda et al., 2022).

Even though the precise etiology of EM is not known, the widely accepted Sampson’s theory of retrograde menstruation suggests that EM lesions originate from refluxed, endometrial fragments deposited during menstruation Sampson, 1927. Both pregnancy and menstruation depend on spontaneous decidualization of endometrial stroma that is extensively remodeled under the influence of hormones, growth factors, and select cytokines that orchestrate immune cell recruitment and vascular adaptions (Gellersen and Brosens, 2014). There is clear evidence that EM patients have defects in eutopic endometrium, including differential expression of key endometrial receptivity markers such as leukemia inhibitory factor (LIF), protein arginine methyltransferase 5 (PRMT5), and homeobox protein hox-A10 (HOXA10), that have been associated with EM and subsequent infertility (Cai et al., 2022; Tomassetti and D’Hooghe, 2018; Zutautas et al., 2023). Evidence also suggests that components of the ECS, including CNR1 and CNR2, are important in maintaining tissue integrity during decidualization and successful implantation of the embryo. Indeed, several reports indicate that mice lacking cannabinoid receptors, CNR1 and CNR2, displayed impaired implantation, increased pregnancy failure rates, heightened edema, and inadequate primary decidual zone formation, highlighting the crucial role of ECS signaling in successful decidualization, implantation, and pregnancy (Wang et al., 2008; Li et al., 2019; Sun et al., 2010).

In EM, CNR1 and CNR2 activation aids in controlling lesion proliferation, pain, and vascularization (Lingegowda et al., 2021a; Leconte et al., 2010). Keeping in view dysregulated ECS signaling and their central role in decidualization and fertility, we hypothesize that altered CNR1 and CNR2 expression will disrupt ECS signaling dynamics, leading to further lesion development. Furthermore, the involvement of ECS in modulating immune response and homeostasis, may disrupt the immune dynamics and foster lesion establishment.

We conducted a comprehensive investigation into the role of the dysregulated ECS in EM establishment and progression by utilizing CNR1 k/o and CNR2 k/o mouse models. To address the underlying causes of ECS dysfunction, we induced artificial decidualization in WT, CNR1 k/o, and CNR2 k/o mice and used the endometrial fragments from decidualized (DD) and undecidualized (UnD) uterine horns to induce EM in recipient mice of their respective genotypes. Furthermore, we explored the immunomodulatory potential of the ECS in EM, shedding light on how alterations in EC signaling may influence immune cell behavior within the localized peritoneal milieu in mice induced with EM. Our study contributes to the foundational knowledge around ECS dysregulation in EM and paves the way for potential therapeutic strategies targeting ECS for disease management.

Emerging evidence from our previously reported findings and others, implicated dysregulation of ECS, comprising CNR1 and CNR2 canonical receptors along with their EC ligands, in EM pathophysiology (Lingegowda et al., 2021b; Sanchez et al., 2016). The ECS is involved in several physiological processes including (but not limited to) pain perception, immune regulation, and reproductive functions Rodríguez de Fonseca et al., 2005; CNR1 and CNR2 are expressed in immune cells, nerve tissues, and serve as critical regulators of reproductive processes including decidualization and embryo implantation (Di Blasio et al., 2012; Walker et al., 2019). The etiology of EM has been speculated to be routed in defective decidualization and retrograde menstruation of the endometrial fragments combined with ECS dysregulation (Lingegowda et al., 2022; Sampson, 1927; Maia et al., 2020). While it is plausible that decreased ECS function influences EM lesion initiation, progression, and severe pain experience, it is not clear whether ECS dysfunction actively contributes to EM pathogenesis, or whether it represents a secondary consequence of alterations occurring within the refluxed endometrial tissue, leading to the establishment of EM lesions.

Keeping this central dogma in view and to provide insights into early events of EM pathogenesis, we induced EM in both CNR1 k/o and CNR2 k/o mice utilizing syngeneic, DD, and UnD uterine endometrial fragments. Absence of CNR1 and CNR2 did not influence systemic levels of ECS ligands but the lesion microenvironment displayed significant changes in the levels of OEA and PEA, suggesting a tissue-specific response.

One intriguing aspect of ECS involvement in EM is its role in decidualization, a process pivotal for uterine receptivity to embryo implantation and successful pregnancy, that may also contribute to EM establishment (Correa et al., 2016). Although both CNR1 and CNR2 are active in decidualization, CNR1 may have a more prominent role. Absence of CNR1 and CNR2 shows compromised decidualization in mice in a CNR1-dependent manner validated through in-vitro studies (Li et al., 2020). Similarly, in our study, EM lesions (both UnD and DD) from mice lacking CNR1 showed significantly more DEGs (2088), compared to CNR2 (287) and WT (2). Genes essential for decidualization such as Igfbp2, Bmp3, Ptgdr, Wnt7a, and Esr1 were downregulated in the DD, EM lesions from CNR1 k/o mice compared to their UnD counterparts. This further reinforces the role of CNR1 in the uterine and EM lesion microenvironment, including their role in decidualization response. Moreover, the interplay between CNR1 and CNR2 are important since CNR2 contributes to immunomodulation, which is a key process during decidualization (Turcotte et al., 2016; Taylor et al., 2010). Even though retrograde menstruation is considered the main mechanism by which endometrial fragments reach the peritoneal cavity and implant to form EM lesions, the retrograded menstrual debris itself does not undergo decidualization. However, some EM lesions in the peritoneal cavity, under the influence of estrogen and progesterone, can undergo decidualization as the lesions can exist in different evolutionary stages, from active red lesions to quiescent white lesions (Leone Roberti Maggiore et al., 2016).

Given the complexity of ECS signaling and compensatory mechanisms, we focused our investigation on the immune dysregulation aspect of EM pathophysiology. Our findings suggest that altered ECS dynamics during decidualization disrupt ECS signaling, leading to dysregulation of immune responses and aberrant cellular behavior. Indeed, immune dysfunction is a hallmark of EM (Symons et al., 2018; Ahn et al., 2015), and ECS could play a crucial role in shaping immune responses, particularly through its impact on T cell function yet there is no clear evidence. Alterations in T cell populations and functions have been associated with EM progression, suggesting their vital role in EM pathogenesis and maintenance (Tanaka et al., 2017; Kyama et al., 2003). Our flow cytometry analysis revealed significant alterations in immune cell populations in mice bearing EM lesions, with a notable absence of CD3 + T cells, CD4 + helper T cells, and CD8 + cytotoxic T cells specifically in CNR2 k/o mice. Mechanistic in-vitro studies further confirmed an aberrant T cell response in CNR2 k/o mice, as with T cell receptor activation and stimulation there was decreased viability. Combined, our findings show that CNR2 is critical in T cell survival upon TCR activation with pathogen-associated molecular patterns (PAMPs)/danger-associated molecular patterns (DAMPs) or antigen-mediated signals. These findings also shed light on a previously unrecognized role of CNR2 in EM-associated adaptive immune dysfunction given the critical role of T cells in immune surveillance and regulation. Furthermore, speculation of EM being a cause of ECS dysfunction could be of importance since CNR2 was found to be reduced in the lesions of EM patients, as shown by our previous study (Lingegowda et al., 2021b). In addition, the bulk RNA sequencing strengthens the finding of dysregulation of T cell-related genes in CNR2 k/o EM lesions. The observed downregulation of T cell-related genes such as Cd3e, Cd3g, Gata3, and Ctla4 is consistent with the diminished CD3 + T cell populations and highlights the relevance of CNR2 in T cell-mediated immune responses within the endometriotic microenvironment.

KEGG pathway analysis of differentially expressed immune-related genes in CNR2 k/o DD lesions further revealed that Th1, Th2, and Th17 cell differentiation pathways were impacted, and the previous literature confirms the dysregulation of these pathways in EM pathophysiology (Chang et al., 2023; Andreoli et al., 2011). Additionally, our in-vitro functional assay showing CD4 + helper T cells being affected (proliferation) more than the CD8 + cytotoxic T cell subset further adds to the subset-specific behaviour of CNR2. Our results provide a missing link between the ECS and immune system functioning during EM.

To gain insights into the early features of lesion initiation and establishment, we conducted an IMC analysis of EM lesions across genotypes and different lesion types (DD and UnD). DD lesions from CNR1 and CNR2 k/o mice showed higher T-cell residing in the lesions with increased stromal compartments and monocytes/macrophages population compared to WT lesions. Stromal cells contribute to the early development of EM lesions by promoting inflammation, angiogenesis, fibrosis, and immune modulation (McKinnon et al., 2022; Queckbörner et al., 2020; Zondervan et al., 2018). Additionally, the interaction between macrophages and stromal cells is important in EM, with the NLRP3 inflammasome playing a role in lesion development (Guo et al., 2021). Studies have implicated macrophages in EM lesion growth where they support angiogenesis (formation of blood vessels) by producing pro-angiogenic factors such as vascular endothelial growth factor (VEGF) (Ding et al., 2012; Sun et al., 2019; McLaren et al., 1996). Given the combined increase in proliferation, endothelial markers, and monocytes/macrophages in EM lesions from mice potentially indicates that they could modulate the early lesion microenvironment in the event of CNR1 and CNR2 dysregulation. Based on the proportion of these macrophages to certain phenotypes, such as M1 or M2, would dictate lesion development and subsequent progression. Further studies are required to tease out molecular interactions of CNR1 and CNR2 with specific immune cell subsets in a complex EM lesion microenvironment and determine how it contributes to the establishment of blood supply and lesion survival.

The dysregulation of the ECS, as evidenced by the altered expression of CNR1 and CNR2 in our mouse model of EM, appears to have far-reaching consequences on the cellular and molecular landscape of endometriotic lesions. Since CNR1 is widely expressed in the central nervous system where it regulates pain perception, mood, and other neurological processes, the dysregulation of CNR1 signaling may impact the sensory innervation and pain responses associated with the EM (Rodríguez de Fonseca et al., 2005). Additionally, CNR1 has been shown to modulate immune cell function, including the production of pro-inflammatory cytokines Klein, 2005. The loss of CNR1 signaling in immune cells infiltrating the endometriotic lesions likely contributes to the altered immune profiles observed in our study. In contrast, CNR2 is predominantly expressed in immune cells, such as macrophages, lymphocytes, and natural killer cells (Turcotte et al., 2016). This receptor plays a crucial role in the regulation of immune responses, including the modulation of cytokine production, cell migration, and proliferation. The significant reduction in CD3 + T cells in the peritoneal cavity and spleen of CNR2 knockout mice suggests that the loss of CNR2 may have a profound impact on T cell homeostasis and function in EM dependent manner, as this was not the case in sham-operated mice. This impairment in T cell function has direct consequences on the adaptive immune response, as evidenced by the altered gene expression profiles and pathways related to immune function in our transcriptomic analysis. But we haven’t conducted specific mechanistic experiments to tease out the interplay between immune response and endometriosis lesion development in our model systems.

Several limitations should be acknowledged in our study. Firstly, understanding the homeostatic aspects of ECS, both with and without the presence of CNR1 and CNR2, remains a complex challenge. While our global k/o mouse models provide valuable insights, further research utilizing targeted k/o specific to the uterus could offer a more precise understanding of their contributions to uterine physiology and further implications in EM establishment. The use of mouse models to study EM has inherent limitations due to species differences and the inability to fully recapitulate the human disease. The molecular and cellular complexities associated with DD and UnD endometrial tissues, as well as the timing of EM induction in these mice, may not perfectly mirror the human condition. No significant baseline alterations were observed in the immune profile between the CNR1 and CNR2 k/o and the WT mice without EM induction. However, the uterine environment has not been assessed to understand the baseline immune profile between the k/o and WT mice. These limitations emphasize the need for future investigations to enhance the translational relevance of our findings and further our understanding of the complex interplay between ECS, decidualization, and EM pathogenesis.

In conclusion, our study offers evidence for the involvement of CNR1 and CNR2 dysregulation in EM pathogenesis. Through an integrative analysis of transcriptomic profiles, immune cell dynamics, and spatial relationships within EM lesions from mice, we unveil the intricate interactions between ECS, immune responses, and cellular changes in EM. By identifying potential mechanisms through which ECS disruption could impact EM, our research provides a foundation for the development of targeted therapies addressing the ECS’s influence on EM. These findings will advance our understanding of EM and lead to innovative therapeutic strategies to manage this complex disorder.

Bulk mRNA sequencing data is provided in the supplementary files (Supplementary Data 4) and IMC data generated in this study has been deposited in Mendeley Data (https://doi.org/10.17632/2ptns5yhzh.2). All the codes used in the current study are from previously published articles, as cited in the text. Authors do not report original code.

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Author details

1. Harshavardhan Lingegowda

   Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Canada

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6030-4936

2. Katherine B Zutautas

   Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Canada

   Contribution

   Data curation, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4304-1024

3. Yuhong Wei

   Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, Canada

   Contribution

   Data curation, Methodology

   Competing interests

   No competing interests declared

4. Priyanka Yolmo

   1. Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Canada
   2. Division of Cancer Biology and Genetics, Queen’s University, Kingston, Canada

   Contribution

   Data curation, Investigation, Methodology

   Competing interests

   No competing interests declared

5. Danielle J Sisnett

   Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Canada

   Contribution

   Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8061-0631

6. Alison McCallion

   Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Canada

   Contribution

   Methodology

   Competing interests

   No competing interests declared

7. Madhuri Koti

   1. Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Canada
   2. Division of Cancer Biology and Genetics, Queen’s University, Kingston, Canada

   Contribution

   Resources, Funding acquisition

   Competing interests

   No competing interests declared

8. Chandrakant Tayade

   Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Canada

   Contribution

   Conceptualization, Resources, Funding acquisition, Writing - review and editing

   For correspondence

   tayadec@queensu.ca

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9062-050X

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