TGF-beta action on leukocyte polarization in sickle cell anemia

• Grant number: 17/14594-0
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): August 01, 2017
• Effective date (End): July 31, 2020
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Nicola Amanda Conran Zorzetto
• Grantee: Lidiane de Souza Torres
• Home Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 14/00984-3 - Red blood cell disorders: pathophysiology and new therapeutic approaches, AP.TEM

Abstract

Sickle cell anemia (SCA) is a hemolytic anemia, caused by the inheritance of hemoglobin S (HbS) in homozygous. Inflammation is a fundamental component of its pathophysiology, and can occur acutely and chronically. In general, numbers and levels of leukocytes and proinflammatory cytokines are high in the disease and these are associated with the clinical severity. In this context, transforming growth factor beta (TGF-beta) is a key cytokine in immune and vascular homeostasis, and its main pathway of action is dependent on signal transducing intracellular proteins (SMADs). Studies show that TGF-beta contributes to the resolution of inflammatory conditions, mainly due to the polarization of neutrophils (N1 to N2) and macrophages (M1 to M2), and that its activity can be stimulated by dimethylsulfoxide (DMSO), which has the ability to increase the availability of receptors on the cell membrane. Thus, the aim of this study is to evaluate the anti-inflammatory effects of TGF-beta1 in SCD and to verify if this action can be upregulated by the stimulation of its canonical signaling pathway with DMSO. For this, neutrophils and macrophages of patients with AF will be isolated and submitted to different treatments with TGF-beta and DMSO, and their activation, polarization, cytokine production and adhesive properties will be evaluated. The most effective treatments will be reproduced in vivo, using Berkeley transgenic mice, an animal model for SCD. The effects of TGF-beta and DMSO on the production of cytokines, as well as on leukocyte recruitment in the microcirculation and vaso-occlusive processes, will be evaluated. The results obtained will contribute to elucidate the participation of TGF-beta and its signaling pathway in SCD, as well as to suggest new treatment strategies to restrict the exacerbation of the inflammatory response in this disease.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CONRAN, NICOLA; TORRES, LIDIANE. cGMP modulation therapeutics for sickle cell disease. Experimental Biology and Medicine, v. 244, n. 2, p. 132-146, FEB 2019. Web of Science Citations: 1.

TORRES, LIDIANE; CONRAN, NICOLA. Emerging pharmacotherapeutic approaches for the management of sickle cell disease. EXPERT OPINION ON PHARMACOTHERAPY, v. 20, n. 2, p. 173-186, JAN 22 2019. Web of Science Citations: 1.