1. NLRP3 Protein Deficiency Exacerbates Hyperoxia-induced Lethality through Stat3 Protein Signaling Independent of Interleukin-1β
- Author
-
Takanori Komada, Koumei Shirasuna, Hideaki Yamasawa, Eicke Latz, Tadayoshi Karasawa, Motoi Kobayashi, Yoichiro Iwakura, Yukihiko Sugiyama, Yoshiko Mizushina, Yoshiyuki Inoue, Masafumi Takahashi, Masashi Bando, Hiroaki Kimura, Tadashi Kasahara, Akira Kawashima, Naoko Mato, and Fumitake Usui
- Subjects
STAT3 Transcription Factor ,Chemokine ,Acute Lung Injury ,Interleukin-1beta ,Respiratory Mucosa ,Hyperoxia ,Lung injury ,Biochemistry ,Mice ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Animals ,Macrophage ,STAT3 ,Molecular Biology ,Mice, Knockout ,integumentary system ,biology ,Molecular Bases of Disease ,Cell Biology ,respiratory system ,Pathophysiology ,In vitro ,respiratory tract diseases ,Pulmonary Alveoli ,Matrix Metalloproteinase 9 ,Proto-Oncogene Proteins c-bcl-2 ,Apoptosis ,Immunology ,biology.protein ,medicine.symptom ,Carrier Proteins ,Signal Transduction - 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 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.
- Published
- 2015