ImportanCe of inflammasOmes in eMerging Environmental Toxin-driven patHologies – COMETH-

The profound changes that global warming is bringing about in the environment include not only the emergence of pathogens, but also various environmental threats, such as marine toxins, which implies the need to determine to what extend our organisms, can adapt to these changes. Specifically, the algal species Vulcanodinium rugosum that was previously restricted to tropical or subtropical waters is now colonizing temperate Atlantic and Mediterranean areas where its produces a toxic metabolite Portimine. This toxin causes skin, eye and lung inflammation and necrosis, which can lead to the extremely pathological consequences in exposed people with more than 2000 cases detected since 2021. In this context, it is of major importance to determine how this environment-driven Portimine production will affect human health and the crtical molecular mechnisms involved. Our preliminary results using primary human skin keratinocytes and airway epithelial cells suggest the involvement of a specific inflammatory complex, the NLRP1 inflammasome, in driving Portimine-dependent pathology.
In this context, we aim to 1/ Decipher the molecular mechanisms by which Portimine activates the NLRP1 inflammasome and the pathophisiological consequences in keratinocytes and in airways epithelial cells, 2/Address the Portimine-induced pathology in human skin/airway organoids and in vivo using zebrafish and 3/ Determine the pharmacological potential of NLRP1 inhibition in Portimine-induced inflammation.
Altogether, this research aims at providing the very first evidence of the total responsibility of the NLRP1 inflammasome axis in the pathology induced by the emerging toxin Portimine, but also aim at offering novel novel therapeutic leads and solutions.