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

• Published in: The Journal of biological chemistry 2015-02, Vol.290 (8), p.5065-5077
• Main Authors: Mizushina, Yoshiko, Shirasuna, Koumei, Usui, Fumitake, Karasawa, Tadayoshi, Kawashima, Akira, Kimura, Hiroaki, Kobayashi, Motoi, Komada, Takanori, Inoue, Yoshiyuki, Mato, Naoko, Yamasawa, Hideaki, Latz, Eicke, Iwakura, Yoichiro, Kasahara, Tadashi, Bando, Masashi, Sugiyama, Yukihiko, Takahashi, Masafumi
• Format: Article
• Language: English
• Subjects: Acute Lung Injury - genetics; Acute Lung Injury - metabolism; Acute Lung Injury - pathology; Animals; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cytokine; Hyperoxia - genetics; Hyperoxia - metabolism; Hyperoxia - pathology; Inflammasome; Inflammation; Interleukin-1beta - metabolism; Lung Injury; Matrix Metalloproteinase 9 - metabolism; Mice; Mice, Knockout; Molecular Bases of Disease; NLR Family, Pyrin Domain-Containing 3 Protein; Proto-Oncogene Proteins c-bcl-2 - metabolism; Pulmonary Alveoli - metabolism; Pulmonary Alveoli - pathology; Respiratory Mucosa - metabolism; Respiratory Mucosa - pathology; Signal Transduction; STAT3 Transcription Factor - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.603217

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 NLRP3 inflammasomes, which regulate IL-1β production and lead to inflammatory responses, in the pathophysiology of HALI; however, their role is not fully understood. In this 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 lungs of NLRP3−/− mice exhibited reduced inflammatory responses, such as inflammatory cell infiltration and cytokine expression, as well as increased and decreased expression of MMP-9 and Bcl-2, respectively. NLRP3−/− mice exhibited diminished expression and activation of Stat3, which regulates MMP-9 and Bcl-2, in addition to increased numbers of apoptotic alveolar epithelial cells. In vitro experiments revealed that alveolar macrophages and neutrophils promoted Stat3 activation in alveolar epithelial cells. Furthermore, NLRP3 deficiency impaired the migration of neutrophils and chemokine expression by macrophages. These findings demonstrate that NLRP3 regulates Stat3 signaling in alveolar epithelial cells by affecting macrophage and neutrophil function independent of IL-1β production and contributes to the pathophysiology of HALI. Background: The role of NLRP3 inflammasomes in hyperoxic acute lung injury (HALI) remains unclear. Results: NLRP3 deficiency exacerbated lethality and diminished Stat3 activation caused by inflammatory cells in a murine HALI model. Conclusion: NLRP3 regulates Stat3 activation by affecting inflammatory cell infiltration independent of IL-1β. Significance: These findings demonstrate the novel role of NLRP3 in Stat3-mediated protective effects against HALI.