title: TLR4-Upregulated IL-1β and IL-1RI Promote Alveolar Macrophage Pyroptosis and Lung Inflammation through an Autocrine Mechanism.
abstract: 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.
authors.affiliation: 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.
authors.forename: Xingying
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Critical Care Medicine, Shanghai First Hospital, Jiaotong University School of Medicine, Shanghai 201600, China.
authors.forename: Yongbing
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Biological Sciences, University of Pittsburgh School of Arts and Science, Pittsburgh, PA 15213, USA.
authors.forename: Erica K
authors.initials: EK
authors.lastname: Fan
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.|Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh PA 15240, USA.
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Liang
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.|McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.|Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh PA 15240, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wilson
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.|Department of Anesthesiology, Shanghai Xinghua Hospital, Jiaotong University School of Medicine, Shanghai 200092, China.
authors.forename: Xueyin
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, 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.
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000378:metabolism; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000502:physiology*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D011014:Pneumonia / Q000276:immunology*; D000069292:Pyroptosis / Q000276:immunology*; D017472:Receptors, Interleukin-1 / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017472:Receptors, Interleukin-1; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4