title: Exposure to cigarette smoke impacts myeloid-derived regulatory cell function and exacerbates airway hyper-responsiveness.
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.
authors.affiliation: Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Tong Huan
authors.initials: TH
authors.lastname: Jin
authors.affiliation: Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Aisha
authors.initials: A
authors.lastname: Farhana
authors.affiliation: Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Freeman
authors.affiliation: Department of Cell Developmental and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Estell
authors.affiliation: Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Jaroslaw W
authors.initials: JW
authors.lastname: Zmijewski
authors.affiliation: Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Gaggar
authors.affiliation: Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.affiliation: Department of Cell Developmental and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Schwiebert
authors.affiliation: 1] Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL, USA [2] KwaZulu-Natal Research Institute for Tuberculosis and HIV, Durban, South Africa.
authors.forename: Adrie J C
authors.initials: AJ
authors.lastname: Steyn
authors.affiliation: Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Jessy S
authors.initials: JS
authors.lastname: Deshane
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D016535:Bronchial Hyperreactivity / Q000209:etiology*; D002478:Cells, Cultured; D000067596:Interleukin-33; D007378:Interleukins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000009:adverse effects*
chemical_list: C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D012906:Smoke; D009569:Nitric Oxide