2. Academic Validation
  3. IQGAP1 domesticates macrophages to favor mycobacteria survival via modulating NF-κB signal and augmenting VEGF secretion

IQGAP1 domesticates macrophages to favor mycobacteria survival via modulating NF-κB signal and augmenting VEGF secretion

  • Int Immunopharmacol. 2024 Sep 10:138:112549. doi: 10.1016/j.intimp.2024.112549.
Xin Wen 1,  Dan Li 2,  Hankun Wang 1,  Ding Zhang 1,  Jingrui Song 1,  Ziwei Zhou 3,  Weifeng Huang 1,  Xuan Xia 1,  Xiaohong Hu 2,  Wei Liu 4,  Jacqueline Gonzales 5,  Laura E Via 5,  Lu Zhang 6,  Decheng Wang 7
Affiliations

Affiliations

  • 1 Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China; Yichang Key Laboratory of Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China.
  • 2 Department of Tuberculosis, The Third People's Hospital of Yichang, Yichang 443003, PR China.
  • 3 State Key Laboratory of Genetic Engineering, Institute of Genetics, MOE Engineering Research Center of Gene Technology, School of Life Science, Fudan University, Shanghai 200433, PR China.
  • 4 The First College of Clinical Medical Science, China Three Gorges University, Yichang, PR China; Institute of Digestive Disease, China Three Gorges University, Yichang, PR China; Department of Gastroenterology, Yichang Central People's Hospital, Yichang, PR China.
  • 5 Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda 20982, MD, USA.
  • 6 State Key Laboratory of Genetic Engineering, Institute of Genetics, MOE Engineering Research Center of Gene Technology, School of Life Science, Fudan University, Shanghai 200433, PR China. Electronic address: zhanglu407@fudan.edu.cn.
  • 7 Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China; Yichang Key Laboratory of Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China. Electronic address: dcwang99@163.com.
PMID: 38944950 DOI: 10.1016/j.intimp.2024.112549
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.

Keywords

Granuloma; IQGAP1; Mycobacteria; Phthiocerol dimycocerosate (PDIM); VEGF.

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