Ingenium 2021
Immunomodulators and macrophages in endometriosis pathogenesis and progression Hilda Jafaraha, Isabelle Chickanoskyb, Alexis Nolfia,c, Mangesh Kulkarnia,c, Clint Skillena,c, Bryan Browna,c a c
Department of Bioengineering, bCarnegie Mellon University, McGowan Institute of Regenerative Medicine
Hilda Jafarah
Hilda Jafarah is a senior bioengineering student who was born and raised in Jeddah, Saudi Arabia. She’s motivated to combine her passion for immunomodulation, tissue engineering, and drug delivery to advance medicine especially in women’s health. After graduation, she aspires to pursue an Md/PhD.
Dr. Bryan Brown is an Associate Professor in the Department of Bioengineering with secondary appointments in the Department of Obstetrics, Gynecology, and Reproductive Sciences and the Clinical and Translational Science Institute at the University of Pittsburgh. He is also Bryan Brown, Ph.D. a core faculty member of the McGowan Institute for Regenerative Medicine where he serves as the Director of Educational Outreach. Dr. Brown is also an Adjunct Assistant Professor of Clinical Sciences at the Cornell University College of Veterinary Medicine and Chief Technology Officer of Renerva, LLC, a Pittsburgh-based start-up company.
Significance Statement
Endometriosis, affecting 200 million women worldwide, causes chronic pelvic pain, infertility, and increases the risk of cancer. This research found that endometriosis development is caused by dysregulated macrophage involvement and subsequent cytokine cascade. This knowledge opens doors to understanding disease identification, potential disease biomarkers, and immunotherapies for diagnosis and treatment.
Category: Review Paper
Keywords: Endometriosis, Cytokines, Macrophages, Pathophysiology, Immune response
Abstract
A comprehensive literature review was conducted focusing on recent findings on the topic of the pathogenesis of endometriosis which is characterized by the ectopic growth of endometrial cells within the peritoneal cavity. Women with endometriosis display a dysfunctional innate and adaptive immune response where immune cells including natural killer cells (NK cells), dendritic cells (DC cells), cytotoxic T cells (T cells), and, specifically, macrophages behave differently. An overpowering imbalance of immunosuppressive factors play a role in the immunoescape of endometrial cells, and the upregulation in angiogenic and neurogenic factors promote the formation and growth of ectopic lesions. With the lack of efficient models, the pathogenesis of endometriosis remains to be unclear; however, current research emphasizes the role of a dysfunctional immune response to refluxed endometrial cells in women with endometriosis including the differential response of immune cells and the expression of various hormones, immunomodulatory cytokines, growth factors, prostaglandins, and angiogenic and neurogenic factors.
1. Introduction
Endometriosis (EMS) is a gynecological disease characterized by the endometrial lining binding outside of the uterine cavity, forming “lesions”. Typically lesions form on the lining of the pelvic cavity (peritoneum) or the organs of the cavity (e.g., ovaries). It is associated with chronic pelvic pain, infertility, and fatigue. EMS affects about 1015% of women of reproductive age, up to 50% of infertile women, and is prevalent in 71–97% of women with chronic pelvic pain [1]; meanwhile, diagnosis is usually delayed by an average of 10 years from the onset of symptoms. Sampson’s theory of retrograde menstruation, defined as the pathogenic reflux of endometrial cells during menses through the fallopian tubes, is commonly accepted to explain the mechanism through which endometrial tissue travels into the peritoneal cavity; however, it fails to explain the discrepancy between the 76-90% of women who experience retrograde menstruation and the 10-15% of women affected by EMS [1]. This literature review allows for a comprehensive understanding of immune malfunction in macrophage and cytokine recruitment in EMS. The macrophage is a unique subset of monocytes with vital roles in both innate and adaptive immunity as it can differentiate into a wide variety of phenotypes ranging from the two extremes: M1 and M2. Pro-inflammatory, “M1-like,” macrophages perpetuate inflammation, secrete pro-inflammatory signaling molecules, and destroy tissues while anti-inflammatory, “M2-like,” macrophages aid in tissue healing and restorative processes. Some studies propose that M1-like macrophages initiate EMS, while others suggest that a localized tissue-level M2-like macrophage population enhances the growth and development of ectopic lesions [2,3]. The hormonal and immune involvement of M1-like and M2-like macrophages during the pathogenesis of EMS recruit various immunomodulators to the peritoneal cavity and result in a cytokine 35
