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Role of the aryl hydrocarbon receptor (AhR) in the pathogenesis of sepsis

Grant number: 12/04076-9
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): June 01, 2012
Effective date (End): May 31, 2015
Field of knowledge:Biological Sciences - Pharmacology - General Pharmacology
Principal researcher:Fernando de Queiroz Cunha
Grantee:Andressa de Freitas Mendes Dionisio
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:11/19670-0 - Mechanisms involved in the pathophysiology of rheumatoid arthritis, pain and sepsis, AP.TEM

Abstract

Sepsis is a systemic inflammatory response resulting from the inability of the host to confine the infection locally. Studies realized in our laboratory demonstrated that the high mortality observed in severe sepsis correlates with the failure of the neutrophil migration to infectious focus and dissemination of infection. The mechanisms involved in neutrophil migration failure are not completely understood. However, it is known that systemic activation of TLRs by bacteria and/or their products results in production of circulating cytokines which stimulate the expression of inducible nitric oxide synthase (iNOS), leading to high amounts of NO, which in turn results in the failure of neutrophil migration. However, animals subjected to a model of non severe sepsis present an efficient neutrophil recruitment to infectious focus by which hosts are able to constrainthe spreading of infection. In this context, recently we demonstrated a direct action of IL-17 mediating the neutrophil recruitment to infection site. Recent reports support that activation of aryl hydrocarbon receptor (AhR), a transcription factor, has a role in immune response. The AHR is expressed by Th17 cells and also by cells from innate immune system, such as gama delta T cells, invariant natural killer T(iNKT) and lymphoid-tissue inducer (LTi)-like cells and is important for their effectors functions, including IL-17 and IL-22 production which are essential to host protection against infection. However, the role of AhR in sepsis it was not demonstrated. An important aspect is that the literature data have shown that the systemic inflammatory response negatively regulates the expression of the AhR. In addition, a recent study demonstrated that NO suppresses the proliferation and function of Th17 cells through the inhibition of the AhR expression. Since, IL-17 plays a critical role in the control of infection, we are hypothesizing that the NO produced during severe sepsis promotes the reduction in the AhR expression and thus suppresses the Th17 cytokine expression pattern, causing spreading of the infection process. In addition, we attempt to verify whether the effects of IL-17 and IL-22 in response to sepsis are dependent on the AhR. (AU)

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