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

Academic Article

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.
  • Published In

    Keywords

  • Adoptive Transfer, Animals, Bone Marrow Cells, Bronchial Hyperreactivity, Cells, Cultured, Interleukin-33, Interleukins, Mice, Mice, Inbred C57BL, Myeloid Cells, NF-kappa B, Nitric Oxide, Reactive Oxygen Species, Smoke, Tobacco
  • Digital Object Identifier (doi)

    Author List

  • Wang Y; Jin TH; Farhana A; Freeman J; Estell K; Zmijewski JW; Gaggar A; Thannickal VJ; Schwiebert LM; Steyn AJC
  • Start Page

  • 1312
  • End Page

  • 1325
  • Volume

  • 94
  • Issue

  • 12