The GTPase Rab1 is required for NLRP3 inflammasome activation and inflammatory lung injury

Yuehui Zhang, Lijun Wang, Yang Lv, Chunling Jiang, Guangyu Wu, Randal O. Dull, Richard D. Minshall, Asrar B. Malik, Guochang Hu

Research output: Contribution to journalArticle

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-κB 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.

Original languageEnglish (US)
Pages (from-to)194-206
Number of pages13
JournalJournal of Immunology
Volume202
Issue number1
DOIs
StatePublished - Jan 1 2019

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Inflammasomes
Interleukin-18
GTP Phosphohydrolases
Lung Injury
Interleukin-1
Sepsis
Macrophages
Alveolar Macrophages
Plasmids
ras Proteins
Lung Transplantation
Bronchoalveolar Lavage Fluid
Punctures
Ligation
Neutrophils
Nucleotides
Adenosine Triphosphate
Cytokines
Brain
Therapeutics

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

The GTPase Rab1 is required for NLRP3 inflammasome activation and inflammatory lung injury. / Zhang, Yuehui; Wang, Lijun; Lv, Yang; Jiang, Chunling; Wu, Guangyu; Dull, Randal O.; Minshall, Richard D.; Malik, Asrar B.; Hu, Guochang.

In: Journal of Immunology, Vol. 202, No. 1, 01.01.2019, p. 194-206.

Research output: Contribution to journalArticle

Zhang, Y, Wang, L, Lv, Y, Jiang, C, Wu, G, Dull, RO, Minshall, RD, Malik, AB & Hu, G 2019, 'The GTPase Rab1 is required for NLRP3 inflammasome activation and inflammatory lung injury', Journal of Immunology, vol. 202, no. 1, pp. 194-206. https://doi.org/10.4049/jimmunol.1800777
Zhang, Yuehui ; Wang, Lijun ; Lv, Yang ; Jiang, Chunling ; Wu, Guangyu ; Dull, Randal O. ; Minshall, Richard D. ; Malik, Asrar B. ; Hu, Guochang. / The GTPase Rab1 is required for NLRP3 inflammasome activation and inflammatory lung injury. In: Journal of Immunology. 2019 ; Vol. 202, No. 1. pp. 194-206.
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