Cigarette smoke destabilizes NLRP3 protein by promoting its ubiquitination

Respir Res. 2017 Jan 5;18(1):2. doi: 10.1186/s12931-016-0485-6.


Background: Cigarette smoke suppresses innate immunity, making smokers more susceptible to infection. The NLRP3 inflammasome is a multi-protein complex that releases interleukin (IL) -1β and IL -18. These cytokines are critical for a timely host response to pathogens. Whether cigarette smoke affects NLRP3 protein levels, and its ability to form an inflammasome, is not known.

Methods and results: Using the human monocyte THP1 cell line and C57BL/6 mice, we show that cigarette smoke decreases NLRP3 levels in cells by increasing ubiquitin-mediated proteasomal processing. Half-life of NLRP3 is shortened with the exposure to cigarette smoke extract. Cigarette smoke extract reduces cellular NLRP3 protein abundance in the presence of lipopolysaccharide, a known inducer of NLRP3 protein, thereby decreasing the formation of NLRP3 inflammasomes. The release of IL-1β and IL-18 by inflammasome activation is also decreased with the exposure to cigarette smoke extract both in THP1 cells and primary human peripheral blood macrophages.

Conclusions: Cigarette smoke extract decreased NLRP3 protein abundance via increased ubiquitin-mediated proteasomal processing. The release of IL-1β and IL-18 is also decreased with cigarette smoke extract. Our findings may provide mechanistic insights on immunosuppression in smokers and unique opportunities to develop a strategy to modulate immune function.

Keywords: Cigarette smoke; NLRP3; Ubiquitin.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Humans
  • Inflammasomes / drug effects*
  • Inflammasomes / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / drug effects
  • Monocytes / immunology*
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology*
  • Smoke / adverse effects*
  • Tobacco Products / adverse effects*
  • Ubiquitination / drug effects
  • Ubiquitination / immunology*


  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Smoke