The role of IL-1b and inflammasome activation in intravascular hemolysis-induced tissue iron accumulation

• Grant number: 24/10726-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: August 01, 2024
• End date: February 28, 2026
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Fernando Ferreira Costa
• Grantee: Pamela Lara de Brito
• Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 19/18886-1 - Pathophysiological mechanisms and treatment of red blood cell abnormalities, AP.TEM

Abstract

In disorders characterized by chronic hemolytic anemia, such as sickle cell disease (SCD), recurrent processes of intravascular hemolysis result in the release of hemoglobin (Hb) and heme. In conditions of chronic intravascular hemolysis, iron regulatory mechanisms are depleted, resulting in iron overload in the plasma and increased tissue iron deposition. This excess of iron in tissues leads to oxidative stress, and inflammatory processes, exacerbating anemia, and causing damage to vital organs. In transgenic animals with SCD and murine models of chronic hemolysis, the liver, spleen, heart, and kidneys are the organs most susceptible to iron accumulation and thus most affected by inflammatory processes resulting from iron overload, leading to fibrosis, cardiomyopathy, and renal failure. Recent findings from our research group suggest that IL-1b, a pro-inflammatory cytokine processed by inflammasomes in macrophage and other myeloid cells, plays a critical role in iron accumulation and damage to vital organs.Additionally, hepcidin, a peptide hormone that regulates iron homeostasis and influences erythropoiesis, may have its regulation and availability affected by IL-1b in SCD. Therefore, the main aim of this project is to investigate the role of IL-1b processing and inflammasome activation in iron accumulation associated with chronic hemolytic disorders, such as SCD. Through the use of cytokine neutralization, pharmacological blockade, and gene silencing (siRNA) strategies, we will evaluate in vitro and in vivo the impact of IL-1b on inflammatory profile, macrophage polarization, expression of iron regulators, anemia markers, iron accumulation, organ damage, as well as investigate inflammasome assembly and its involvement in the pathophysiological mechanism. With this study, we aim to generate intellectual property that could be commercially exploited, contributing to the development of new treatments for iron overload, a complication with few therapeutic options currently available.