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

• Alternative Title:
  Xenobiotica
• Personal Author:
  Lin, Chen-Chung ; Law, Brandon F. ; Hettick, Justin M.
• 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 |/|. 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 |/| KLF4, or M2 macrophage-associated markers (|, |), and chemokines (|) were measured by either RT-qPCR, western blot, or luciferase assay. 3. MDI-GSH exposure downregulates |/| by 1.46- to 9.75-fold whereas upregulates | by 1.68- to 1.99-fold, respectively. | analysis predicts binding between | and | Gain- and loss-of-function, luciferase reporter assays and RNA-induced silencing complex-immunoprecipitation (RISC-IP) studies confirm the posttranscriptional regulatory roles of | and | in macrophages. Furthermore, |/| regulate the expression of M2 macrophage-associated markers and chemokines | KLF4. 4. In conclusion, | play a major role in regulation of MDI/MDI-GSH-induced M2 macrophage-associated markers and chemokines by targeting the | transcript, and KLF4-mediated regulation in macrophages.
• Subjects:
  Chemokines Humans Isocyanates Kruppel-Like Factor 4 Kruppel-Like Transcription Factors Macrophage Activation Macrophages MicroRNAs Up-Regulation
• Keywords:
  4,4’-methylene Diphenyl Diisocyanate (MDI) Diisocyanates (dNCOs) Krüppel-Like Factor 4 (KLF4) MicroRNAs (miRs) Occupational Asthma (OA)
• Source:
  Xenobiotica. 54(9):730-748
• Pubmed ID:
  38568505
• Pubmed Central ID:
  PMC11489325
• Document Type:
  Journal Article
• Funding:
  CC999999/ImCDC/Intramural CDC HHSUnited States/
• Volume:
  54
• Issue:
  9
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:e2e067e95c01ca1651567cf9e23e3191ad9fb2360ccd979d6a403cd0b6212f7d8835e6555114516b998390b9f035ae5a61dfac5345cfb873a4bcdbf939e47c63
• Download URL:
  https://stacks.cdc.gov/view/cdc/166695/cdc_166695_DS1.pdf
• File Type:
  [PDF - 3.94 MB ]