Exposure to cigarette smoke impacts myeloid-derived regulatory cell function and exacerbates airway hyper-responsiveness

Lab Invest. 2014 Dec;94(12):1312-25. doi: 10.1038/labinvest.2014.126. Epub 2014 Nov 3.

Abstract

Cigarette smoking enhances oxidative stress and airway inflammation in asthma, the mechanisms of which are largely unknown. Myeloid-derived regulatory cells (MDRC) are free radical producing immature myeloid cells with immunoregulatory properties that have recently been demonstrated as critical regulators of allergic airway inflammation. NO (nitric oxide)-producing immunosuppressive MDRC suppress T-cell proliferation and airway-hyper responsiveness (AHR), while the O2(•-) (superoxide)-producing MDRC are proinflammatory. We hypothesized that cigarette smoke (CS) exposure may impact MDRC function and contribute to exacerbations in asthma. Exposure of bone marrow (BM)-derived NO-producing MDRC to CS reduced the production of NO and its metabolites and inhibited their potential to suppress T-cell proliferation. Production of immunoregulatory cytokine IL-10 was significantly inhibited, while proinflammatory cytokines IL-6, IL-1β, TNF-α and IL-33 were enhanced in CS-exposed BM-MDRC. Additionally, CS exposure increased NF-κB activation and induced BM-MDRC-mediated production of O2(•-), via NF-κB-dependent pathway. Intratracheal transfer of smoke-exposed MDRC-producing proinflammatory cytokines increased NF-κB activation, reactive oxygen species and mucin production in vivo and exacerbated AHR in C57BL/6 mice, mice deficient in Type I IFNR and MyD88, both with reduced numbers of endogenous MDRC. Thus CS exposure modulates MDRC function and contributes to asthma exacerbation and identifies MDRC as potential targets for asthma therapy.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Animals
  • Bone Marrow Cells / physiology
  • Bronchial Hyperreactivity / etiology*
  • Cells, Cultured
  • Interleukin-33
  • Interleukins / biosynthesis
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cells / physiology*
  • NF-kappa B / physiology
  • Nitric Oxide / biosynthesis
  • Reactive Oxygen Species / metabolism
  • Smoke / adverse effects*
  • Tobacco / adverse effects*

Substances

  • Il33 protein, mouse
  • Interleukin-33
  • Interleukins
  • NF-kappa B
  • Reactive Oxygen Species
  • Smoke
  • Nitric Oxide