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MicroRNA-Mediated Krüppel-Like Factor 4 Upregulation Induces Alternatively Activated Macrophage-Associated Marker and Chemokine Transcription in 4,4’-Methylene Diphenyl Diisocyanate Exposed Macrophages
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9 2024
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Source: Xenobiotica. 54(9):730-748
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Alternative Title:Xenobiotica
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Personal Author:
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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.
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Pubmed ID:38568505
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Pubmed Central ID:PMC11489325
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Volume:54
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Issue:9
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[PDF-3.94 MB]
