Neutrophils initiate proinflammatory immune responses in early endometriosis lesion development
Taylor R. Wilson, Kurt R. Peterson, Stephanie A. Morris, Damaris Kuhnell, Susan Kasper, Katherine A. Burns
Taylor R. Wilson, Kurt R. Peterson, Stephanie A. Morris, Damaris Kuhnell, Susan Kasper, Katherine A. Burns
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Research Article Immunology Inflammation Reproductive biology

Neutrophils initiate proinflammatory immune responses in early endometriosis lesion development

Abstract

Endometriosis is a chronic gynecological disease that affects 1 in 10 reproductive-aged women. Most studies investigate established disease; however, the initiation and early events in endometriotic lesion development remain poorly understood. Our study used neutrophils from human menstrual effluent from patients with and without endometriosis for immunophenotyping, and it used a mouse model of endometriosis and a mouse endometriosis cell line to determine the role of neutrophils in the initiating events of endometriosis, including attachment and survival of minced endometrial pieces. In menstrual effluent from women with endometriosis, the ratios of aged and proangiogenic neutrophils increased compared with controls, indicating a potentially permissive proinflammatory microenvironment. In our endometriosis mouse model, knocking down neutrophil recruitment with α-CXCR2 into the peritoneum decreased endometrial tissue adhesion — supported by decreased levels of myeloperoxidase and neutrophil elastase in both developing lesions and peritoneal fluid. Fibrinogen was identified as the preferred substrate for endometrial cell adhesion in an in vitro adhesion assay and in developing lesions in vivo. Together, aged and proangiogenic neutrophils and their secretions likely promote attachment and formation of endometriotic lesions by releasing neutrophil extracellular traps and upregulating fibrinogen expression as a provisional matrix to establish attachment and survival in the development of endometriosis lesions.

Authors

Taylor R. Wilson, Kurt R. Peterson, Stephanie A. Morris, Damaris Kuhnell, Susan Kasper, Katherine A. Burns

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Figure 8

mEmLe cells adhere to fibronectin in a neutrophil dependent manner, and the same fibrinogen response is observed in attaching lesion tissue.

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mEmLe cells adhere to fibronectin in a neutrophil dependent manner, and ...
(A) mEmLe cells were used in an adhesion array with fibronectin, collagen I, collagen IV, laminin I, and fibrinogen. Cells were allowed to adhere in the presence of peritoneal fluid from I:I, I:α, α:I, and α:α groups where I = IgG and α = α-CXCR2. n = 4 representative of 3 independent experiments. (B) Fibrinogen (Fgb) gene expression in minced endometrial pieces, attaching (att), and unattached (unatt) lesions from I uterus, α uterus I:I, I:α, α:I, and α:α groups. I uterus (n = 3), α uterus (n = 5), I:I att (n = 5), I:I unatt (n = 5), I:α att (n = 7), I:α unatt (n = 4), α:I att (n = 5), α:I unatt (n = NA), α:α att (n = NA), and α:α unatt (n = 10) for attaching and unattached lesions of biological replicates from 2 independent experiments. (C) Thrombospondin (Thbs1) gene expression in minced endometrial pieces and lesions from I uterus (n = 3), α uterus (n = 4), I:I (n = 11), I:α (n = 9), α:I (n = 7), and α:α (n = 9) groups. n = 3–5 for minced endometrial pieces, n = 11–17 for lesions of biological replicates from 2 independent experiments. NA = no gene expression. Data represent ± SEM. Statistical significance for each graph was determined nonparametric, Kruskal-Wallis followed with 1-tailed Mann-Whitney U tests. Letters different from each other are statistically significant. P ≤ 0.05.