Altered p16Ink4a, IL-1β, and Lamin b1 Protein Expression Suggest Cellular Senescence in Deep Endometriotic Lesions.

Helena Malvezzi,Sérgio Podgaec,Laura Palmieri Da Silva E Sousa,Helen Mendes Do Nascimento,Renee Zon Filippi,Carla Azevedo Piccinato,Juliana Meola,Cristine Dobo

doi:10.3390/ijms23052476

Abstract

Endometriosis causes immunological and cellular alterations. Endometriosis lesions have lower levels of lamin b1 than the endometrium. Moreover, high levels of pro-inflammatory markers are observed in the peritoneal fluid, follicular fluid, and serum in endometriosis lesions. Thus, we hypothesized that the accumulation of senescent cells in endometriosis tissues would facilitate endometriosis maintenance in an inflammatory microenvironment. To study senescent cell markers and the senescence-associated secretory phenotype (SASP) in endometriosis lesions, we conducted a cross-sectional study with 27 patients undergoing video laparoscopy for endometriosis resection and 19 patients without endometriosis. Endometriosis lesions were collected from patients with endometriosis, while eutopic endometrium was collected from patients both with and without endometriosis. Tissues were evaluated for senescence markers (p16Ink4a, lamin b1, and IL-1β) and interleukin concentrations. The expression of p16Ink4a increased in lesions compared to that in eutopic endometrium from endometriosis patients in the secretory phase. In the proliferative phase, lesions exhibited lower lamin b1 expression but higher IL-4 expression than the eutopic endometrium. Further, IL-1β levels were higher in the lesions than in the eutopic endometrium in both the secretory and proliferative phases. We believe that our findings may provide targets for better therapeutic interventions to alleviate the symptoms of endometriosis.

Highlights

Endometriosis is a chronic inflammatory gynecological disease with no clear etiology [1]
We investigated a plethora of cellular senescence markers and the senescence-associated secretory phenotype (SASP) in deep endometriosis lesions and eutopic endometrium
Senescent cells accumulate in a given organ or tissue and may favor a pro-inflammatory environment, thereby decreasing the regenerative capacity of the cell and favoring the appearance of several diseases, such as cancer, degenerative diseases, and aging syndromes; this is known as chronic senescence [33]

Summary

Introduction

Endometriosis is a chronic inflammatory gynecological disease with no clear etiology [1]. Apoptosis resistance, angiogenesis increase [8,9], and proliferative capacity [10] are influenced by high concentrations of pro-inflammatory cytokines and growth factors, such as transforming growth factor, interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor (TNF), interferon-gamma [11–13], and by recruitment of immune system cells, such as macrophages [14], natural killer cells [15,16], and neutrophils [17,18]. It is unclear whether this inflammatory pattern is a cause or a consequence of the implantation and development of endometrial tissue outside the uterus. Senescent cells remain active indefinitely, synthesizing metabolites that characterize the senescence-associated secretory phenotype (SASP) [23,24]

Methods

Results

Conclusion