The role of ectonucleotidases and adenosine in the establishment of sepsis-induced immunosuppression

• Grant number: 12/10100-0
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): September 01, 2012
• Effective date (End): August 29, 2017
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: José Carlos Farias Alves Filho
• Grantee: Daniele Carvalho Bernardo Nascimento
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID
• Associated scholarship(s): 15/25974-3 - The role of ectonucleotidase CD39 in the establishment of sepsis-induced immunosuppression, BE.EP.PD

Abstract

Sepsis is a systemic inflammatory response caused by an infection, which is characterized by tissue injury, extensive apoptosis and immune dysfunction, is regularly accompanied by the development of a pronounced immunosuppression. The establishment of immunosuppression in sepsis involves the production of inflammatory mediators, alternatively activated macrophages (M2 macrophages) and an increased of regulatory T cells (Tregs) numbers, which impairs the proliferation and function of effector T cells and leads to increased susceptibility to secondary infection. The adenosine is a purine nucleoside that has been implicated in modulating the inflammatory response. Recently, it was demonstrated that the adenosine promotes alternatively activated macrophages via A2-type adenosine receptors. Furthermore, adenosine produced by Treg has been implicated as an important mediator of the suppressive effect of these cells on the function of effectors T cells. In this way, M2 macrophages and Treg cells have high expression on their surface of both ectonucleotidases CD39/ENTPD1 and CD73/ecto-52-nucleotidase, enzymes that generate ADO through ATP degradation. High levels of serum adenosine have been observed in septic patients. However, it is unclear the role of ectonucleotidases and adenosine in the development of sepsis-induced immunosuppression. In this way, the objective of this project is to determine the involvement of ectonucleotidases and adenosine in the establishment of sepsis-induced immunosuppression. We will intend to investigate whether ectonucleotidases (CD39 and CD73) and adenosine are responsible for inducing increased differentiation of M2 macrophages, increased frequency of Treg and an impaired proliferative capacity of effector T cells. Our results will contribute to a better understanding of the mechanisms involved in the pathophysiology of sepsis, and might contribute to the development of a new therapy for this disease that still lacks an effective treatment.