Hypoxia-Inducible Factor Signaling in Macrophages Promotes Lymphangiogenesis in Leishmania major Infection
| Autor: | Tiffany Weinkopff, Jessica Surma, M. Celeste Simon, Hayden Roys, Humphrey Wanjala, Gopinath Venugopal, Anne K. Bowlin, Manjunath Bettadapura |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
CD4-Positive T-Lymphocytes
0301 basic medicine Myeloid Aryl hydrocarbon receptor nuclear translocator Immunology Leishmaniasis Cutaneous Biology Microbiology 03 medical and health sciences 0302 clinical medicine Basic Helix-Loop-Helix Transcription Factors medicine Macrophage Leishmania major Lymphangiogenesis Macrophages Aryl Hydrocarbon Receptor Nuclear Translocator Hypoxia (medical) biology.organism_classification Vascular endothelial growth factor A 030104 developmental biology Infectious Diseases medicine.anatomical_structure Lymphatic system 030220 oncology & carcinogenesis Host-Pathogen Interactions Cancer research Parasitology Disease Susceptibility Fungal and Parasitic Infections medicine.symptom Biomarkers Signal Transduction |
| Zdroj: | Infect Immun |
| ISSN: | 1098-5522 0019-9567 |
| DOI: | 10.1128/iai.00124-21 |
| Popis: | Vascular remodeling is a phenomenon seen in the cutaneous lesions formed during infection with Leishmania parasites. Within the lesion, Leishmania major infection leads to the infiltration of inflammatory cells, including macrophages, and is associated with hypoxic conditions and lymphangiogenesis in the local site. This low-oxygen environment is concomitant with the expression of hypoxic inducible factors (HIFs), which initiate the expression of vascular endothelial growth factor-A (VEGF-A) in macrophages during the infection. Here, we found that macrophage hypoxia is elevated in the skin, and the HIF target Vegfa is preferentially expressed at the site of infection. Further, transcripts indicative of both HIF-1α and HIF-2α activation were increased at the site of infection. Given that HIF mediates VEGF-A and that VEGF-A/VEGFR-2 signaling induces lymphangiogenesis, we wanted to investigate the link between myeloid HIF activation and lymphangiogenesis during L. major infection. We show that myeloid aryl hydrocarbon receptor nuclear translocator (ARNT)/HIF/VEGF-A signaling promotes lymphangiogenesis (the generation of newly formed vessels within the local lymphatic network), which helps resolve the lesion by draining away inflammatory cells and fluid. Concomitant with impaired lymphangiogenesis, we find the deletion of myeloid ARNT/HIF signaling leads to an exacerbated inflammatory response associated with a heightened CD4(+) Th1 immune response following L. major infection. Altogether, our data suggest that VEGF-A-mediated lymphangiogenesis occurs through myeloid ARNT/HIF activation following Leishmania major infection and this process is critical in limiting immunopathology. |
| Databáze: | OpenAIRE |
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