Chronic Stress Blocks the Endometriosis Immune Response by Metabolic  Reprogramming

Chong Lu; Jing Xu; Ke Li; Jing Wang; Yilin Dai; Yiqing Chen; Ranran Chai; Congjian Xu; Yu Kang

doi:10.3390/ijms25010029

Endometriosis · Pathophysiology

Chronic Stress Blocks the Endometriosis Immune Response by Metabolic Reprogramming

Lu C, Xu J, Li K, Wang J, Dai Y, Chen Y, Chai R, Xu C, Kang Y

Published December 19, 2023 International Journal of Molecular Sciences, 25(1)

DOI 10.3390/ijms25010029 PMID 38203209 PMC PMC10778859

RRM Academy Synopsis

Chronic stress is linked to different genes in endometriosis lesions

Lesions from patients with chronic stress showed 1381 genes with different activity. Surgical lesions from patients with depression and anxiety were compared with lesions from patients with neither. Gene testing used 5 lesions per group and metabolite testing used 15 per group, and immune and metabolic pathways differed.

Key Findings

Of 30 patients with surgically confirmed endometriosis, the chronic stress group scored 5 or above on both depression and anxiety questionnaires. Controls had neither anxiety nor depression on the same scales.
Among 34,757 expressed genes in 5 lesions per group, 1381 mRNAs differed between groups. In the chronic stress group, 689 of these were up-regulated and 692 were down-regulated.
Metabolite testing of all 30 samples detected 3629 known metabolites. Of these, 235 differed between the groups (p < 0.05), in pathways such as glutathione and arginine and proline metabolism.
Real-time PCR on 10 samples matched the microarray: six mRNAs (CXCR4, GABARAPL1, IL-7R, STAT4, CD14, CCR5) were lower and two (GATM, GSTM2) higher with chronic stress (p < 0.05).
The authors report that amino acids such as arginine and serine accumulated more highly in lesions of the chronic stress group, while several immune-related pathways were down-regulated.

Interpretation

The study compared lesion tissue collected at surgery from 30 patients at one hospital. Tissue was collected once, so the results describe group differences at a single time point. Chronic stress meant questionnaire scores for depression and anxiety, and gene testing used 5 lesions per group. The authors conclude that stress may block the immune response in endometriosis through metabolic reprogramming. They state that the exact mechanism remains to be researched. Only patients with endometriosis were studied.

RRM Context

Restorative reproductive medicine treats endometriosis as a disease of the body and removes it at the source by excision surgery. Care also looks after the person living with it. The paper's introduction cites earlier work reporting that patients with deep-infiltrating pain may have very high chronic stress, which surgical treatment can in many cases relieve. Stress and lesion biology sit in one clinical picture.

Our editorial summary of this paper, not the article's abstract.

Abstract

Studies have shown that the occurrence and development of endometriosis are closely linked to long-term psychological stress. The specific contribution of chronic stress to the metabolic adaptations in patients with endometriosis is still unknown. Lesions were removed from ten endometriosis patients during an operation, and the participants were divided into two groups using a psychological questionnaire. An mRNA Human Gene Expression Microarray analysis was applied to compare the mRNA expression profiles between the chronic stress group and the control group. In addition, the reliability of the mRNA Human Gene Expression Microarray analysis was verified by using research on metabolites based on both the liquid chromatography (LC-MS/MS) technique and quantitative reverse transcription polymerase chain reaction (RT-PCR). A microarray analysis of significantly up-regulated, differentially expressed genes between the chronic stress and the control groups showed genes that were principally related to metabolism-related processes and immune-related processes, such as the immune response process, negative regulation of T cell proliferation, the leucine metabolic process, and the L-cysteine metabolic process (p < 0.05). LC-MS showed that the differential metabolites were primarily concerned with arginine and proline metabolism, D-glutamine and D-glutamate metabolism, aspartate metabolism, glycine, serine metabolism, and tyrosine metabolism (p < 0.05). The possibility of chronic stress blocks the endometriosis immune response through metabolic reprogramming. Chronic stress reduces the supply of energy substrates such as arginine and serine, down-regulates T immune cell activation, and affects the anti-tumor immune response, thereby promoting the migration and invasion of endometriosis lesions in patients with chronic stress.

Topics

Endometriosis › Pathophysiology › Inflammation and Immunology · Lifestyle and Environment › Stress and Allostatic Load › Cortisol and the Adrenal Axis

Chong Lu, Jing Xu, Ke Li, Jing Wang, Yilin Dai, Yiqing Chen, Ranran Chai, Congjian Xu, Yu Kang

C Lu, J Xu, K Li, J Wang, Y Dai, Y Chen, R Chai, C Xu, Y Kang

PMID 38203209 38203209 DOI 10.3390/ijms25010029 10.3390/ijms25010029 Lu et al. 2023, Lu 2023

Keywords

Arginine, RNA, Messenger, Serine