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Sci Rep. 2016 Aug 16;6:31663. doi: 10.1038/srep31663.

TLR4-Upregulated IL-1β and IL-1RI Promote Alveolar Macrophage Pyroptosis and Lung Inflammation through an Autocrine Mechanism.

He X1,2, Qian Y3, Li Z2, Fan EK4, Li Y2,5, Wu L1,2, Billiar TR2,6, Wilson MA2,5, Shi X1,7, Fan J2,5,6.

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Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Department of Critical Care Medicine, Shanghai First Hospital, Jiaotong University School of Medicine, Shanghai 201600, China.
Department of Biological Sciences, University of Pittsburgh School of Arts and Science, Pittsburgh, PA 15213, USA.
Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh PA 15240, USA.
McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Department of Anesthesiology, Shanghai Xinghua Hospital, Jiaotong University School of Medicine, Shanghai 200092, China.


Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome (MODS) following pulmonary infection. Alveolar macrophages (AM) are at the center of the pathogenesis of the development of ALI. Interleukin-1β (IL-1β) is one of the key pro-inflammatory mediators, and its maturation is tightly controlled by the formation and activation of the inflammasome. The biological effects of IL-1β are mediated through IL-1 receptor (IL-1R). In this study, we investigated the influence of LPS-induced IL-1β release and IL-1RI upregulation on the development of lung inflammation. We demonstrated that in AM, LPS-TLR4 signaling not only activates Nlrp3 inflammasome activation and subsequent release of IL-1β, but also up-regulates IL-1RI expression on AM surface through MyD88 and NF-κB dependent signaling. The upregulated IL-1RI, therefore, sensitizes AM to IL-1β and results in pyroptosome formation, which in turn leads to AM pyroptosis, a type of caspase-1-dependent inflammatory cell death. We further showed that AM pyroptosis exaggerates lung inflammation. The present study demonstrates a novel mechanism underlying LPS-induced innate immunity; that is, a secondary upregulation of IL-1β-IL-1RI signaling is responsible for AM pyroptosis and augmented lung injury in response to LPS.

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