NLRP6 plays a key role in pulmonary inflammation to chronic ozone through activation of pyroptotic and necroptotic pathways - 20/03/24
Résumé |
Introduction |
Ground-level ozone is an important gaseous constituent of air pollution that contributes to lung disease progression and mortality. Ozone exposure in mice causes pulmonary inflammation evolving into lung emphysema and/or fibrotic patterns but the mechanisms are not well understood [1 ]. We investigated the role of the poorly characterized innate receptor nucleotide-binding domain and leucine-rich repeat containing protein 6 (NLRP6) involved in inflammasome scaffold [2 ], in ozone exposure-induced in the context of immunogenic cell death [3 ].
Methods |
Using a chronic ozone exposure model of chronic obstructive pulmonary disease (COPD) in mice, we investigated the role of the NLRP6 receptor in pulmonary inflammation, emphysema and fibrosis by exposing wild-type, Nlrp6 deficient mice and mice deficient for Nlrp6 specifically in lung epithelial cells. In addition, we analyzed NLRP6 expression in lung using NLRP6 FLAG-tagged mice. NLRP6-dependent expression and/or activation of proteins characteristic of immunological cell deaths such as pyroptosis, apoptosis and necroptosis were analyzed by western blotting and immunofluorescence.
Results |
We observed that mouse chronic ozone exposure increased NLRP6 expression in bronchial and alveolar epithelial cells and in a lesser extend in airway macrophages. Interestingly Nlrp6 deficiency dampened pulmonary inflammation and alveolar damage with reduced neutrophil and eosinophil influxes, attenuated chemokine/cytokine and remodeling factor production, collagen deposition and lung fibrosis. Chronic ozone-induced a loss of alveolar type 1 pneumocytes that was attenuated in Nlrp6 deficient mice. Mechanistically, we report that chronic ozone exposure promoted NLRP6-dependent caspase-1, caspase-11 and gasdermin D activation in alveolar type 1 pneumocytes. Chronic ozone exposure also induced NLRP6-dependent expression of apoptotic and necroptotic markers in lung tissue.
Conclusion |
We identified NLRP6 as a new innate sensor of chronic ozone-induced lung injury promoting pulmonary inflammation leading to emphysema and fibrosis in mice. Our results suggest that chronic ozone induces pulmonary inflammation through NLRP6 inflammasome-dependent pyroptosis and necroptosis of alveolar type 1 pneumocytes. Understanding the mechanisms of pollutant-induced alveolar cell death, lung inflammation and repair might help fight COPD and lung fibrosis.
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Vol 41 - N° 3
P. 204 - mars 2024 Retour au numéroDéjà abonné à cette revue ?