MicroRNA-Mediated Krüppel-Like Factor 4 Upregulation Induces Alternatively Activated Macrophage-Associated Marker and Chemokine Transcription in 4,4′-Methylene Diphenyl Diisocyanate Exposed Macrophages

Details

• Personal Author:
  Hettick JM ; Law, Brandon F. ; Lin C-C
• Description:
  1. Occupational exposure to 4,4'-methylene diphenyl diisocyanate (MDI) is associated with occupational asthma (OA) development. Alveolar macrophage-induced recruitment of immune cells to the lung microenvironment plays an important role during asthma pathogenesis. Previous studies identified that MDI/MDI-glutathione (GSH)-exposure downregulates endogenous hsa-miR-206-3p/hsa-miR-381-3p. Our prior report shows that alternatively activated (M2) macrophage-associated markers/chemokines are induced by MDI/MDI-GSH-mediated Krüppel-Like Factor 4 (KLF4) upregulation in macrophages and stimulates immune cell chemotaxis. However, the underlying molecular mechanism(s) by which MDI/MDI-GSH upregulates KLF4 remain unclear. 2. Following MDI-GSH exposure, microRNA(miR)-inhibitors/mimics or plasmid transfection, endogenous hsa-miR-206-3p/hsa-miR-381-3p, KLF4, or M2 macrophage-associated markers (CD206, TGM2), and chemokines (CCL17, CCL22, CCL24) were measured by either RT-qPCR, western blot, or luciferase assay. 3. MDI-GSH exposure downregulates hsa-miR-206-3p/hsa-miR-381-3p by 1.46- to 9.75-fold whereas upregulates KLF4 by 1.68- to 1.99-fold, respectively. In silico analysis predicts binding between hsa-miR-206-3p/hsa-miR-381-3p and KLF4. Gain- and loss-of-function, luciferase reporter assays and RNA-induced silencing complex-immunoprecipitation (RISC-IP) studies confirm the posttranscriptional regulatory roles of hsa-miR-206-3p/hsa-miR-381-3p and KLF4 in macrophages. Furthermore, hsa-miR-206-3p/hsa-miR-381-3p regulate the expression of M2 macrophage-associated markers and chemokines via KLF4. 4. In conclusion, hsa-miR-206-3p/hsa-miR-381-3p play a major role in regulation of MDI/MDI-GSH-induced M2 macrophage-associated markers and chemokines by targeting the KLF4 transcript, and KLF4-mediated regulation in macrophages. [Description provided by NIOSH]
• Subjects:
  Asthma, Occupational Blood Immune System Isocyanates Lung Macrophages Occupational Health Respiratory System Safety
• Keywords:
  4,4'-methylene Diphenyl Diisocyanate 4,4-Methylene Diphenyl Diisocyanate Author Keywords: Occupational Asthma Diisocyanates DNCOs Immune Reaction KLF4 Krüppel-like Factor 4 Lung Cells MDI MicroRNAs MiRs Molecular Signaling OA Occupational Asthma Pathogenesis

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• ISSN:
  0049-8254
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  54
• Issue:
  9
• NIOSHTIC Number:
  nn:20069511
• Citation:
  Xenobiotica 2024 Sep; 54(9):730-748
• Contact Point Address:
  Chen-Chung Lin, Ph.D., NIOSH/HELD/ACIB, 1095 Willowdale Rd., MS L4020, Morgantown, WV, 26505
• Email:
  mjy2@cdc.gov
• CAS Registry Number:
  Diphenylmethane diisocyanate (CAS RN 101-68-8)
• Federal Fiscal Year:
  2024
• Peer Reviewed:
  True
• Source Full Name:
  Xenobiotica
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:498dd6a54ba98f3ee29c86758e1430370fb8601c7ab13b1735212fe87fc4700a3faf349f8b6ce1513821cf266830310267be67c0afabda4070eaf89958519bff
• Download URL:
  https://stacks.cdc.gov/view/cdc/207941/cdc_207941_DS1.pdf
• File Type:
  [PDF - 5.63 MB ]