NLRP3 Inflammasome Activation in Lung Vascular Endothelial Cells Contributes to Intestinal Ischemia/Reperfusion-Induced Acute Lung Injury

• DOI: 10.4049/jimmunol.2000217
• Publication Date: 2020-07-29T20:35:55Z
• Authors: Homare Ito; Hiroaki Kimura; Tadayoshi Karasawa; Shu Hisata; Ai Sadatomo; Yoshiyuki Inoue; Naoya Yamada; Emi Aizawa; Erika Hishida; Ryo Kamata; Takanori Komada; Sachiko Watanabe; Tadashi Kasahara; Takuji Suzuki; Hisanaga Horie; Joji Kitayama; Naohiro Sata; Kazuyo Yamaji-Kegan; Masafumi Takahashi
• Keywords: Inflammation; Male; 0303 health sciences; Inflammasomes; Acute Lung Injury; Caspase 1; Interleukin-1beta; Endothelial Cells; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Reperfusion Injury; NLR Family, Pyrin Domain-Containing 3 Protein; Animals; Lung

Abstract Intestinal ischemia/reperfusion (I/R) injury is a life-threatening complication that leads to inflammation and remote organ damage. The NLRP3 inflammasome regulates the caspase-1–dependent release of IL-1β, an early mediator of inflammation after I/R injury. In this study, we investigated the role of the NLRP3 inflammasome in mice with intestinal I/R injury. Deficiency of NLRP3, ASC, caspase-1/11, or IL-1β prolonged survival after intestinal I/R injury, but neither NLRP3 nor caspase-1/11 deficiency affected intestinal inflammation. Intestinal I/R injury caused acute lung injury (ALI) characterized by inflammation, reactive oxygen species generation, and vascular permeability, which was markedly improved by NLRP3 deficiency. Bone marrow chimeric experiments showed that NLRP3 in non–bone marrow–derived cells was the main contributor to development of intestinal I/R-induced ALI. The NLRP3 inflammasome in lung vascular endothelial cells is thought to be important to lung vascular permeability. Using mass spectrometry, we identified intestinal I/R-derived lipid mediators that enhanced NLRP3 inflammasome activation in lung vascular endothelial cells. Finally, we confirmed that serum levels of these lipid mediators were elevated in patients with intestinal ischemia. To our knowledge, these findings provide new insights into the mechanism underlying intestinal I/R-induced ALI and suggest that endothelial NLRP3 inflammasome–driven IL-1β is a novel potential target for treating and preventing this disorder.