Journal
SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep31663
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Funding
- National Institutes of Health Grant [R01-HL-079669, R56-HL-123882]
- National Institutes of Health Center Grant [P50-GM-53789]
- VA Merit Award [1I01BX002729]
- Key Program of Medical Science Development of PLA [BWS12J027]
- National Natural Science Foundation of China [81372103]
- Shanghai Pujiang Program [15PJD003]
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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-1 beta (IL-1 beta) 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-1 beta are mediated through IL-1 receptor (IL-1R). In this study, we investigated the influence of LPS-induced IL-1 beta 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-1 beta, but also up-regulates IL-1RI expression on AM surface through MyD88 and NF-kappa B dependent signaling. The upregulated IL-1RI, therefore, sensitizes AM to IL-1 beta 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-1 beta-IL-1RI signaling is responsible for AM pyroptosis and augmented lung injury in response to LPS.
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