An emerging role for neutrophils in the pathogenesis of endometriosis

Endometriosis is a debilitating disease which negatively impacts the lives of affected patients, both mentally and physically. The early initiation of the disease is influenced by immune cell interactions. Although less is known about some of the early interactions,mouse models have been illuminating for determining early disease initiation mechanisms. During each menstrual period, retrograde menstruation provides a potential opportunity to expose the peritoneal cavity to immune cells and viable endometrial tissues which may promote an exacerbation and p rogression of the disease. The mechanisms of how lesions are formed is unclear, but recent research shows that immune cell responses are heavily implicated in disease pathogenesis and may be the key to understanding this disease. Neutrophils are thefirst responders and likely play a key role in early responses to lesion formation and clearance of retrograde menstruation. The release of VEGF is one way that neutrophils can promote angiogenesis and lesion development. Although other cells like macrophages aid in the remodeling and neo- vascularization, the effects of neutrophils are still a factor in the early stages. Cytokines like IL6 and CXCL8/IL8 are found at abnormal levels in endo- metriosis. Both of these cytokines affect neutrophil recruitment and alter the peritoneal cavity microenvironment. Currently, determining which cyto- kine has the greatest influence on neutrophils is difficult due to crosstalk and temporal limitations of studying neu trophil surveillance. In addition, N E T o s i sm a yb eal a r g ef a c t o ri nt h ep athogenesis of endometriosis. With more NETs found in endometriosis patients, evidence supports that the functions may differentiate healthy women from women with endome- triosis. Whether NETs are the primary driving force or whether the mul- tifactorial actions of neutrophils work in conjunction to promote disease, it is apparent that neutrophils are an understudied aspect of early disease initiation and progression, thus highlighting the critical need to determine all of the roles of this important cell type. Determining the speci fics of neutrophil and immune functions in e ndometriosis may provide insight into potential non-surgical diagnoses or treatment targets. Neutrophils, along with other immune cells, may be the key to finding the potential biomarkers needed for earlier diagnoses and understanding this complex disease. Data availability No datasets were generated or analyzed during the current study. Received: 26 September 2024; Accepted: 30 January 2025;

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Sources of support to K.A.B. include NIH R01 HD097597 and the University of Cincinnati College of Medicine Startup. The funders played no role in the interpretations found in or writing of this manuscript. Author contributions The Burns Laboratory studies neutrophils in endometriosis (K.A.B.). T.R.W. wrote the first draft of the review article. K.A.B., S.K., and T.R.W. revised, added, critiqued, and reformatted the manuscript. Thefigure was drawn by T.R.W. and S.K. All authors read and approved the final manuscript. Competing interests The authors declare no competing interests. Additional information Correspondenceand requests for materials should be addressed to Katherine A. Burns. Reprints and permissions informationis available at http://www.nature.com/reprints Publisher’s noteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modi fied the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party

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