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Influence of Stress on the Vitamin D-Vitamin D Receptor System, Macrophages, and the Local Inflammatory Milieu in Endometriosis

Abstract

We previously demonstrated the negative impact of stress in an animal model of endometriosis. Although its role is unclear, altered levels of vitamin D (VitD) have been found in patients with this condition. VitD signaling through the VitD receptor (VDR) has anti-proliferative properties and induces an anti-inflammatory phenotype in macrophages. We hypothesized that stress impacts the vitamin D-VDR system, influencing macrophage behavior and the local inflammatory milieu in endometriosis. Endometriosis was surgically induced in female Sprague-Dawley rats, which were then exposed to uncontrollable, controllable, or no stress for 10 days. Sham controls received sutures only. VitD levels were measured by ELISA; cytokine levels by multiplex assay and PCR; and VDR expression and macrophage numbers assessed by immunohistochemistry and immunofluorescence. VDR expression in patient samples was assessed by immunohistochemical staining of a tissue microarray. Serum VitD levels were higher in endometriosis animals compared with sham (p < 0.01) with no significant effect of stress. Uncontrollable stress increased macrophage infiltration (p < 0.01) and VDR expression in vesicles, which were attenuated by controllable stress. Macrophage infiltration correlated with vesicle area (p < 0.05), and peritoneal vitamin D levels correlated with vesicle VDR expression (r = 0.81, p < 0.01). Decreased expression of chemokine ligand 2 (p < 0.05) and TGFβ was observed in endometriosis with uncontrollable stress, whereas IL12 increased with controllable stress. Differential expression of VDR was observed in patient tissues. Stress exacerbates development of cysts in endometriosis through mechanisms that include macrophage recruitment, cytokine changes, and a potentially perturbed VitD:VDR axis, suggesting an impact on the local inflammatory environment.

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Acknowledgements

The authors would like to acknowledge the technical support of Inevy Seguinot and Yadmarie Rivera. Also, thanks to Alcira Benítez for histological preparation and analysis. The endometriosis TMA was constructed with funds from U56CA126379 and we would like to acknowledge the assistance of the staff in the H. Lee Moffitt Cancer Center imaging core.

Funding

These studies were supported in part by R15AT006373 (CBA), R25 GM096955 (AL), R25GM082406 (SH & RAI), and G12MD007579-12 (Behavioral Core Laboratory) from the National Institutes of Health (NIH).

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Correspondence to Caroline B. Appleyard.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the Institutional Animal Care and Use Committee at Ponce Health Sciences University (Animal Welfare Assurance D16-00352).

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Electronic Supplementary Material

Supplementary Table 1

Tissue samples included in Tissue Micro Array (PPTX 51 kb)

Supplementary Fig. 1

Vitamin D receptor correlates with estrogen receptor expression. A significant negative correlation between VDR and estrogen receptor (ER) alpha was found in endometrium glands of both (A) controls (p < 0.01) and (B) patients (p < 0.01). A significant negative correlation with ER beta (p < 0.05) was only found in (D) patients, and not in (C) controls. No significant correlations with progesterone receptor (PR) were found in the glands of either controls (E) or patients (F) (PPTX 387 kb)

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Lopez, A., Cruz, M.L., Chompre, G. et al. Influence of Stress on the Vitamin D-Vitamin D Receptor System, Macrophages, and the Local Inflammatory Milieu in Endometriosis. Reprod. Sci. 27, 2175–2186 (2020). https://doi.org/10.1007/s43032-020-00235-1

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Keywords

  • Endometriosis
  • Macrophage
  • Rat
  • Stress
  • Vitamin D
  • Vitamin D receptor