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Mechanisms involved in activation of dendritic cells and monocytes upon sickle cell anemia

Grant number: 22/01755-4
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): March 01, 2022
Effective date (End): February 29, 2024
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Renata Sesti Costa
Grantee:Matheus Ajeje de Souza
Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated research grant:19/09704-7 - Dendritic cells in Sickle Cell Anemia: molecular mechanisms involved in regulating inflammation and adaptive immune response, AP.JP

Abstract

Sickle cell anemia (SCA) is one of the most common hemoglobinopathies around the world. Patients affected by SCA have a reduced quality of life due to complications resulting from changes in the shape and physical properties of erythrocytes. These complications consist of chronic hemolytic anemia, pain crises, organ dysfunction, susceptibility to infections, among others. Patients with SCA have intravascular hemolysis, in which hemoglobin and its product, heme, are released into the circulation, causing oxidative stress and an inflammatory cascade. Haptoglobin and hemopexin, which normally remove free hemoglobin and heme from the blood, respectively, are dramatically reduced in these patients. Heme oxygenase 1 (HO-1) is a stress-induced enzyme that plays an important role in the detoxification of heme, degrading it into iron, carbon monoxide (CO) and biliverdin, which confer an additional cytoprotective, anti-inflammatory and antioxidant effect. HO-1 has been identified as an immunomodulator of DCs. The induction of HO-1 promotes tolerogenic DCs by inhibiting their pro-inflammatory functions, and for this reason, they have been the target of studies for the treatment of inflammatory diseases. Our preliminary data show that patients with SCA have a higher amount and proportion of total DCs and inflammatory DCs (CD14+) in their blood when compared to healthy subjects, which correlated with an increase in Th17 response and a reduction in regulatory T cells. In the present work, we intend to investigate the molecular mechanisms involved in the activation of these cells, mainly the involvement of HO-1 in the process. The results obtained will provide us with further knowledge about the DC activation and its consequences for the inflammatory process of the disease. DC activation pathways and the factors that stimulate tolerogenic DCs, with consequent regulation of the immune response, have therapeutic potential for treating the chronic inflammation of SCA.

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