Structural mechanism for inflammasome activation and pyroptosis in endometriosis stromal cells

• Grant number: 23/02248-1
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: August 01, 2023
• End date: July 19, 2024
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal Investigator: Sérgio Podgaec
• Grantee: Helena Malvezzi
• Supervisor: Christoph Andreas Diebolder
• Host Institution: Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE). Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE). São Paulo , SP, Brazil
• Institution abroad: Charité - Universitätsmedizin Berlin, Germany
• Associated to the scholarship: 22/10279-1 - Inflammasomes activation in the inflammatory response of deep endometriotic lesions from patients with endometriosis, BP.PD

Abstract

Inflammasomes are macromolecular structures present in the cytoplasm of active immune cells that lead to the activation of caspases and, therefore, the elaboration of an inflammatory response. Activation of caspase-1 results in the release of interleukins (IL-) 1B and 18 and induction of cell death by pyroptosis through maturation of cytosolic proteins of the gasdermin family (GSDM). Deregulation in the activation of inflammation is described in the pathogenesis of several inflammatory diseases, including endometriosis. In endometriosis, a chronic inflammation is the focal molecular and cellular process, responsible for the main symptoms of pain, tissue remodeling, lesions formation, fibrosis and infertility. Endometriosis is a benign gynecological disease that affects around 10% of the female population and, being a chronic inflammatory disease, inflammation plays a fundamental role in the maintenance, survival´s control, proliferation of cellular responses, and cells fate and maintenance. Given the great impact of the activation of inflammasomes on the inflammatory response, changes in their activity are related to inflammatory distress. Therefore, the recognition and understanding of the regulation of inflammasomes are a promising path for basic as well as translational research, especially for endometriosis. Cryo electron microscopy (cryoEM) has been established as method of choice in structural biology as it allows to study macromolecular assemblies at up to atomic resolution in a close to native state. Moreover, cryo electron tomography (cryo-ET) is emerging as a technique to study these assemblies in situ as it enables preservation of the cellular context . Cryo fluorescence microscopy guided in situ cryo-ET of FIB milled cellular lamella could give unprecedented insights into inflammasome formation which in turn might have major impact on understanding and treatment of endometriosis. (AU)