Acute 4,4′-Methylene Diphenyl Diisocyanate Exposure-Mediated Downregulation of miR-206-3p and miR-381-3p Activates Inducible Nitric Oxide Synthase Transcription by Targeting Calcineurin/NFAT Signaling in Macrophages

Details

• Alternative Title:
  Toxicol Sci
• Personal Author:
  Lin, Chen-Chung ; Law, Brandon F. ; Hettick, Justin M.
• Description:
  Exposure to 4,4'-methylene diphenyl diisocyanate (MDI) in the occupational setting may lead to development of occupational asthma (OA), and the underlying molecular mechanisms of MDI-induced disease pathogenesis remain an active area of research. Using a nose-only mouse inhalation model, we find that circulating microRNA (miR)-206-3p and miR-381-3p are downregulated after MDI exposure; however, cellular miR-206-3p and miR-381-3p responses after MDI aerosol exposure and their pathophysiological roles in MDI-OA are unknown. We hypothesize that miR-206-3p and miR-381-3p-regulated mechanisms cause increased expression of the inducible nitric oxide synthase (iNOS) after MDI aerosol exposure. We examined cellular miR-206-3p and miR-381-3p, calcineurins, nuclear factors of activated T cells (NFATs), and iNOS levels from both nose-only exposed murine bronchoalveolar lavage cells (BALCs) and differentiated THP-1 macrophages treated with MDI-glutathione (GSH) conjugates. Both in vivo murine MDI aerosol exposure and in vitro MDI-GSH exposures in THP-1 macrophages result in downregulation of endogenous miR-206-3p and miR-381-3p and upregulation of PPP3CA and iNOS expression. Transfection of THP-1 macrophages with miR-inhibitor-206-3p and miR-inhibitor-381-3p resulted in the upregulation of PPP3CA and iNOS. Using RNA-induced silencing complex immunoprecipitation and translational reporter assays, we verified that PPP3CA, but not iNOS, is directly targeted by both miR-206-3p and miR-381-3p. Downregulation of miR-206-3p and miR-381-3p following by MDI exposure induces calcineurin/NFAT signaling-mediated iNOS transcription in macrophages and BALCs.
• Subjects:
  Animals Antigens Asthma, Occupational Calcineurin Down-Regulation Female Isocyanates Leukocyte Count Macrophages Mice MicroRNAs Nitric Oxide Synthase Type II Occupational Exposure

  More +
• Keywords:
  4,4′-methylene Diphenyl Diisocyanate (MDI) Calcineurin/NFAT Signaling Diisocyanates (dNCOs) INOS Occupational Asthma (OA) PPP3CA
• Source:
  Toxicol Sci. 173(1):100-113
• Pubmed ID:
  31609387
• Pubmed Central ID:
  PMC6944756
• Document Type:
  Journal Article
• Funding:
  CC999999/ImCDC/Intramural CDC HHSUnited States/
• Volume:
  173
• Issue:
  1
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:1823edbda073a294a94a8744504f4597fd151ef6c365cff7544734e2ef1b6472
• Download URL:
  https://stacks.cdc.gov/view/cdc/84055/cdc_84055_DS1.pdf
• File Type:
  [PDF - 2.10 MB ]