The interplay between the nervous system and the immune system has been studied for the past thirty years, but our knowledge of the regulation of the immune system by the sympathetic nervous system (SNS) remains incomplete. Cells of the innate immune system, including macrophages, express both ± and ² adrenergic receptors, which enables them to respond to adrenergic signals from the sympathetic nervous system (SNS) in the immune microenvironment. Following activation by pathogens or pathogen associated molecular patterns (PAMPs), innate immune cells elicit broad changes in their transcriptional program mainly activated by nuclear factor (NF)-kB, activator protein (AP)-1 and interferon regulatory factor (IRF) family transcription factors. Although stimuli from the SNS were initially thought to broadly suppress the ability of macrophages to activate NF-kB- and IRF-dependent transcription, more recent evidence suggests that the SNS more selectively regulates specific genes. Indeed, we find that while beta-adrenergic agonists inhibit several NF-kB-dependent transcripts, unexpectedly, IL-1beta (Il1b) transcript and protein are super-induced in stimulated macrophages in the presence of bbeta-agonist. Since IL-1beta requires inflammasome activation, the objective of this project is to study the regulation of inflammasome activation by the SNS. Inflammasomes are cytosolic complexes composed of 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-1² and IL-18, two prototypical inflammatory cytokines that protect against a variety of pathogens. We hypothesize that adrenergic stimuli regulate inflammasomes during the priming phase, by inducing the paradoxical activation of NF-ºB within the IL-1beta promoter and/or enhancer. Herein, we propose to evaluate the molecular mechanisms by which adrenergic stimuli induce inflammasome activation.
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