151. IQGAP1 domesticates macrophages to favor mycobacteria survival via modulating NF-κB signal and augmenting VEGF secretion.
- Author
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Wen X, Li D, Wang H, Zhang D, Song J, Zhou Z, Huang W, Xia X, Hu X, Liu W, Gonzales J, Via LE, Zhang L, and Wang D
- Subjects
- Animals, Mice, MAP Kinase Kinase 3 metabolism, MAP Kinase Kinase 3 genetics, Mice, Inbred C57BL, Mycobacterium Infections, Nontuberculous immunology, Mycobacterium Infections, Nontuberculous microbiology, Mycobacterium Infections, Nontuberculous metabolism, p38 Mitogen-Activated Protein Kinases metabolism, RAW 264.7 Cells, Transcription Factor RelA metabolism, Tumor Necrosis Factor-alpha metabolism, Macrophages immunology, Macrophages metabolism, Macrophages microbiology, NF-kappa B metabolism, ras GTPase-Activating Proteins metabolism, ras GTPase-Activating Proteins genetics, Signal Transduction, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor A genetics
- Abstract
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), still ranks among the leading causes of annual human death by infectious disease. Mtb has developed several strategies to survive for years at a time within the host despite the presence of a robust immune response, including manipulating the progression of the inflammatory response and forming granulomatous lesions. Here we demonstrate that IQGAP1, a highly conserved scaffolding protein, compartmentalizes and coordinates multiple signaling pathways in macrophages infected with Mycobacterium marinum (Mm or M.marinum), the closest relative of Mtb. Upregulated IQGAP1 ultimately suppresses TNF-α production by repressing the MKK3 signal and reducing NF-κBp65 translocation, deactivating the p38MAPK pathway. Accordingly, IQGAP1 silencing and overexpression significantly alter p38MAPK activity by modulating the production of phosphorylated MKK3 during mycobacterial infection. Pharmacological inhibition of IQGAP1-associated microtubule assembly not only alleviates tissue damage caused by M.marinum infection but also significantly decreases the production of VEGF-a critical player for granuloma-associated angiogenesis during pathogenic mycobacterial infection. Similarly, IQGAP1 silencing in Mm-infected macrophages diminishes VEGF production, while IQGAP1 overexpression upregulates VEGF. Our data indicate that mycobacteria induce IQGAP1 to hijack NF-κBp65 activation, preventing the expression of proinflammatory cytokines as well as promoting VEGF production during infection and granuloma formation. Thus, therapies targeting host IQGAP1 may be a promising strategy for treating tuberculosis, particularly in drug-resistant diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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