A Gender-Dependent Molecular Switch of Inflammation via MyD88/Estrogen Receptor-Alpha Interaction

• Main Authors: El Sabeh R, Bonnet M, Le Corf K, Lang K, Kfoury A, Badran B, Hussein N, Virard F, Treilleux I, Le Romancer M, Lebecque S, Manie S, Coste I, Renno T
• Format: Article
• Language: English
• Published: Dove Medical Press 2021-05-01
• Series: Journal of Inflammation Research
• Subjects: nuclear receptor; post-translational modification; inflammation; protein-protein-interaction
• Online Access: https://www.dovepress.com/a-gender-dependent-molecular-switch-of-inflammation-via-myd88estrogen--peer-reviewed-fulltext-article-JIR

Rana El Sabeh,1,2 Mélanie Bonnet,1 Katy Le Corf,1 Kevin Lang,1 Alain Kfoury,1 Bassam Badran,2 Nader Hussein,2 Francois Virard,1 Isabelle Treilleux,3 Muriel Le Romancer,1 Serge Lebecque,1 Serge Manie,1 Isabelle Coste,1,* Toufic Renno1,* 1Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France; 2Université Libanaise, PRASE, Hadath, Lebanon; 3Pathology Department, Centre Léon Bérard, Lyon, France*These authors contributed equally to this workCorrespondence: Toufic Renno; Isabelle CosteCentre de Recherche en Cancétologie de Lyon, 28 Rue Laennec, Lyon, 69373, FranceTel [phone]; [phone]Email [e-mail] ; [e-mail]: Most Toll-like receptors and IL-1/IL-18 receptors activate a signaling cascade via the adaptor molecule MyD88, resulting in NF-κB activation and inflammatory cytokine and chemokine production. Females are less susceptible than males to inflammatory conditions, presumably due to protection by estrogen. The exact mechanism underlying this protection is unknown.Methods: MCF7 cells expressing wild-type or mutated LXXLL motif were used to determine MyD88/estrogen receptor (ER)-a interaction by immunoprecipitation and cell activation by ELISA and luciferase reporter assay. IL-1b and/or E2 were used to activate MCF7 cells expressing normal or knocked down levels of PRMT1. Finally, in situ proximity ligation assay with anti-MyD88 and anti-methylated ER-a (methER-a) antibodies was used to evaluate MyD88/methylated ER-a interaction in THP1 cells and histological sections.Results: We show that MyD88 interacts with a methylated, cytoplasmic form of estrogen receptor-alpha (methER-α). This interaction is required for NF-κB transcriptional activity and pro-inflammatory cytokine production, and is dissociated by estrogen. Importantly, we show a strong gender segregation in gametogenic reproductive organs, with MyD88/methER-α interactions found in testicular tissues and in ovarian tissues from menopausal women, but not in ovaries from women age 49 and less – suggesting a role for estrogen in disrupting this complex in situ.Discussion: Collectively, our results indicate that the formation of MyD88/methER-α complexes during inflammatory signaling and their disruption by estrogen may represent a mechanism that contributes to gender bias in inflammatory responses.Keywords: nuclear receptor, post-translational modification, inflammation, protein-protein-interaction