Influence of Stress on the Vitamin D-Vitamin D Receptor System, Macrophages, and the Local Inflammatory Milieu in Endome
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ORIGINAL ARTICLE
Influence of Stress on the Vitamin D-Vitamin D Receptor System, Macrophages, and the Local Inflammatory Milieu in Endometriosis Abdon Lopez 1 & Myrella L. Cruz 2 & Gladys Chompre 3 & Siomara Hernández 2 & Raymond A. Isidro 2 & Idhaliz Flores 2 & Caroline B. Appleyard 2 Received: 15 January 2020 / Revised: 1 May 2020 / Accepted: 8 June 2020 # Society for Reproductive Investigation 2020
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. Keywords Endometriosis . Macrophage . Rat . Stress . Vitamin D . Vitamin D receptor
Abdon Lopez and Myrella L. Cruz contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s43032-020-00235-1) contains supplementary material, which is available to authorized users. * Caroline B. Appleyard [email protected] Abdon Lopez [email protected] Myrella L. Cruz [email protected]
Idhaliz Flores [email protected] 1
Department of Biology, University of Puerto Rico, Ponce Campus, Ponce, PR, USA
2
Department of Basic Sciences, Physiology Division, Ponce Health Sciences University-Medical School and Ponce Research Institute, 395 Zona Ind Reparada 2, Ponce, PR 00716-2347, USA
3
Biology and Biotechnology Department, Pon
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