NLRP3 Protein Deficiency Exacerbates Hyperoxia-induced Lethality through Stat3 Protein Signaling Independent of Interleukin-1β

Abstract Supplemental oxygen inhalation is frequently used to treat severe respiratory failure; however, prolonged exposure to hyperoxia causes hyperoxic acute lung injury (HALI), which induces acute respiratory distress syndrome and leads to high mortality rates. Recent investigations suggest the possible role of nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasomes, which regulate interleukin-1β (IL-1β) production and lead to inflammatory responses, in the pathophysiology of HALI; however, their role is not fully understood. In the present study, we investigated the role of NLRP3 inflammasomes in mice with HALI. Under hyperoxic conditions, NLRP3−/− mice died at a higher rate compared with wild-type and IL-1β−/− mice, and there was no difference in IL-1β production in their lungs. Under hyperoxic conditions, the lung of NLRP3−/− mice exhibited reduced inflammatory responses, such as inflammatory cell infiltration and cytokine expression as well as increased and decreased expression of matrix metalloproteinase (MMP)-9 and Bcl-2, respectively. NLRP3−/− mice exhibited diminished expression and activation of signal transducer and activator of transcription 3 (Stat3), which regulates MMP-9 and Bcl-2. In vitro experiments revealed that alveolar macrophages and neutrophils promoted Stat3 activation in alveolar epithelial cells. Furthermore, NLRP3 deficiency impaired the migration of neutrophils as well as chemokine expression by macrophages. These findings demonstrate that NLRP3 regulates Stat3 signaling in alveolar epithelial cells by affecting macrophage and neutrophil function independently of IL-1β production and contributes to the pathophysiology of HALI.