Identification des sirtuines en tant que nouvelles cibles thérapeutiques pour l'asthme allergique

Sirtuins comprise a unique class of NAD+-dependent deacetylases that regulate diverse biological functions including ageing, metabolism and stress resistance. Recently, it has been shown that sirtuins may dampen the inflammatory response in vitro by inhibiting pro-inflammatory transcription factors such as NF-κB. We therefore sought to determine whether sirtuins play a role in allergic airway inflammation. To address this issue, we have assessed in OVA-sensitized mice the effects of selectively antagonizing sirtuins during OVA challenge. Sirtuin inhibition was achieved by treating mice with either cambinol or sirtinol, two selective pharmacological inhibitors. Surprisingly, sirtuin inhibition was associated with strong attenuation of allergic lung inflammation, airway hyperreactivity, production of mucus and Th2 cytokines. We furthermore showed that sirtuin inhibition altered maturation and migration of lung dendritic cells, thereby preventing dendritic cell-driven Th2 priming in the draining lymph nodes. In an attempt to elucidate the mechanisms responsible for these effects we used peroxisome proliferator-activated receptor-γ deficient cells to demonstrate that the effects of cambinol and sirtinol in dendritic cells were dependent on an increase in the activity of this anti-inflammatory transcription factor. Finally, using genetic engineering, we demonstrate that sirtuin 1 is the sirtuin responsible for repression of the activity of PPAR-γ- in dendritic cells, thereby favoring their maturation toward a pro-Th2 phenotype. This study reveals a previously unappreciated function of sirtuin 1 in the regulation of dendritic cell function and Th2 responses, thus shedding new light on our current knowledge on the regulation of inflammatory processes by sirtuins.