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Characterization of sympathetic nervous system regulation on inflammasome activation

Grant number: 16/08180-6
Support Opportunities:Scholarships in Brazil - Post-Doctorate
Effective date (Start): January 01, 2017
Effective date (End): January 01, 2021
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Alexandre Salgado Basso
Grantee:Filipe Menegatti de Melo
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil


The interplay between the Nervous System (NS) and the immune system (IS) has been studied during the last thirty years. In particular, the regulation of the immune system by the Sympathetic Nervous System (SNS) has received a lot of attention. Immune cells express both alfa and beta adrenergic receptors, which enables them to respond to SNS stimulus. The objective of this project is to study whether or not (and how) the SNS can regulate inflammasome activation. Inflammasomes are cytosolic complexes composed by a NLR (Nod-Like Receptor), the adaptor protein ASC and Caspase-1. Inflammasome activation leads to Caspase-1 activation which promotes functional maturation of IL-1beta and IL-18, two prototypical inflammatory cytokines. Eventually, inflammasome activation leads to pyroptosis, an inflammatory cell death. Inflammasomes are essential for protection against a variety of pathogens. Inflammasome activation comprehends two phases: a priming phase, in which NF-kappaB activation leads to pro-IL-1beta and NLRP3 transcription, and an activation phase, in which an agonist that is specific for each NLR promotes the oligomerization of inflammasome components and Caspase-1 activation. There is a great deal of evidence in the literature suggesting that the SNS can regulate inflammasome activation mainly by beta2 adrenergic receptor activation. The SNS could potentially regulate inflammasomes in the priming phase, since beta2 receptor signaling is known to inhibit NF-kappaB activation. On the other hand, no one has shown any regulation by the SNS on the activation phase, although there are some signaling pathways that are good candidates. Evaluate the molecular mechanisms underlying how the SNS could regulate both phases of inflammasome activation, including models of in vitro and in vivo infection, is our main objective. (AU)

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