The GTPase Rab1 Is Required for NLRP3 Inflammasome Activation and Inflammatory Lung Injury

J Immunol. 2019 Jan 1;202(1):194-206. doi: 10.4049/jimmunol.1800777. Epub 2018 Nov 19.

Abstract

Uncontrolled inflammatory response during sepsis predominantly contributes to the development of multiorgan failure and lethality. However, the cellular and molecular mechanisms for excessive production and release of proinflammatory cytokines are not clearly defined. In this study, we show the crucial role of the GTPase Ras-related protein in brain (Rab)1a in regulating the nucleotide binding domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and lung inflammatory injury. Expression of dominant negative Rab1 N124I plasmid in bone marrow-derived macrophages prevented the release of IL-1β and IL-18, NLRP3 inflammasome activation, production of pro-IL-1β and pro-IL-18, and attenuated TLR4 surface expression and NF-кB activation induced by bacterial LPS and ATP compared with control cells. In alveolar macrophage-depleted mice challenged with cecal ligation and puncture, pulmonary transplantation of Rab1a-inactivated macrophages by expression of Rab1 N124I plasmid dramatically reduced the release of IL-1β and IL-18, neutrophil count in bronchoalveolar lavage fluid, and inflammatory lung injury. Rab1a activity was elevated in alveolar macrophages from septic patients and positively associated with severity of sepsis and respiratory dysfunction. Thus, inhibition of Rab1a activity in macrophages resulting in the suppression of NLRP3 inflammasome activation may be a promising target for the treatment of patients with sepsis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytokines / metabolism
  • Disease Models, Animal
  • Humans
  • Inflammasomes / metabolism*
  • Inflammation Mediators / metabolism
  • Lipopolysaccharides / immunology
  • Lung Injury / immunology*
  • Macrophage Activation / genetics
  • Macrophages, Alveolar / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mutation / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Neutrophils / immunology
  • Pneumonia / immunology*
  • Sepsis / immunology*
  • rab1 GTP-Binding Proteins / genetics
  • rab1 GTP-Binding Proteins / metabolism*

Substances

  • Cytokines
  • Inflammasomes
  • Inflammation Mediators
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • rab1 GTP-Binding Proteins