Interferon Regulatory Factor-1 Mediates Alveolar Macrophage Pyroptosis During LPS-Induced Acute Lung Injury in Mice

Shock. 2016 Sep;46(3):329-38. doi: 10.1097/SHK.0000000000000595.

Abstract

Previously, we demonstrated that pyroptosis in alveolar macrophages (AMs) plays an essential role in lipopolysaccharide (LPS)-induced acute lung injury. However, the underlying mechanism remains largely unclear. Here, we show that the absence of interferon regulatory factor 1 (IRF-1) in genetic knock-out mice strongly abrogates pyroptosis in AMs and alleviates the LPS-induced lung injury and systemic inflammation. Our study demonstrates that IRF-1 contributes to caspase-1 activation and apoptosis-associated speck-like protein containing a caspase activation and recruitment domain pyroptosome formation in AMs and leads to downstream inflammatory cytokine release, including that of IL-1β, IL-18, and HMGB1. The nuclear translocation of IRF-1 is linked to the presence of toll-like receptor 4 (TLR4). Our findings suggest that pyroptosis and the downstream inflammatory response in AMs induced by LPS is a process that is dependent on TLR4-mediated up-regulation of IRF-1. In summary, IRF-1 plays a key role in controlling caspase-1-dependent pyroptosis and inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / blood
  • Acute Lung Injury / chemically induced*
  • Acute Lung Injury / immunology
  • Acute Lung Injury / metabolism*
  • Animals
  • HMGB1 Protein / blood
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / metabolism*
  • Interleukin-18 / blood
  • Interleukin-1beta / blood
  • Lipopolysaccharides / toxicity*
  • Macrophages, Alveolar / metabolism*
  • Macrophages, Alveolar / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • Pyroptosis / genetics
  • Pyroptosis / physiology*

Substances

  • HMGB1 Protein
  • Interferon Regulatory Factor-1
  • Interleukin-18
  • Interleukin-1beta
  • Lipopolysaccharides