Reduced Hif1-alpha and VEGFA signaling in STAT3-Hyper IgE Syndrome during S. aureus infection
LECHNER A. 1, EFFNER R. 1, GALINDEZ G. 2,3, KUNERT I. 1,4, MITTWEG T. 1,4, BIRK C. 1,4, ROTHENFUSSER S. 5, VOLZ T. 6, HAGL B. 1, WANTIA N. 7, SCHWIERZECK V. 8, KACPROWSKI T. 2,3, RENNER E. 1,4
1 Translational Immunology in Environmental Medicine, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany; 2 Division Data Science in Biomedicine, Peter L. Reichertz Institute for Medical Informatics of TU Braunschweig and Hannover Medical School, Braunschweig, Germany; 3 Braunschweig Integrated Centre of Systems Biology (BRICS), TU Braunschweig, Braunschweig, Germany; 4 Department of Pediatrics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany; 5 Division of Clinical Pharmacology, Klinikum der Universitaet Muenchen, Munich, Germany; 6 Department of Dermatology and Allergology, School of Medicine, Technical University of Munich, Munich, Germany; 7 Institute of Medical Microbiology, Immunology and Hygiene, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany; 8 Institute of Hygiene, University Hospital Muenster, Muenster, Germany
Connective tissue and vascular abnormalities are complications in patients with STAT3-Hyper-IgE Syndrome (STAT3-HIES). STAT3-HIES is caused by heterozygous mutations in the signal transducer and activator of transcription 3 (STAT3) gene and presents with recurrent Staphylococcus aureus (S. aureus) infections, impaired wound-healing and reduced Th17 immunity. S. aureus modulates hypoxic signaling and angiogenesis by hypoxia-inducible factor 1 alpha (Hif1-alpha) and vascular endothelial growth factor A (VEGFA). Besides hypoxia, interleukin-17 (IL-17) and transforming growth factor beta (TGF-beta) activate Hif1-alpha.
To assess Hif1-alpha and VEGFA signaling during S. aureus infection in fibroblasts and thereby evaluating effects these infections have on the vascular system of STAT3-HIES patients.
Clinical data, microbial colonialization and laboratory data including VEGFA serum levels were assessed in molecularly defined STAT3-HIES patients and healthy subjects. Primary skin fibroblasts of STAT3-HIES patients and healthy subjects were infected with S. aureus (MW2) or stimulated with the Hif1-alpha stabilizer cobalt chloride (CoCl2), IL-17 or TGF-beta and Hif1-alpha target gene expression, including VEGFA, was assessed by gene expression and protein analyses.
The majority of STAT3-HIES patients had elevated blood pressure and showed reduced VEGFA serum levels compared to healthy subjects. After S. aureus infection and CoCl2 stimulation gene levels of the Hif1-alpha signaling pathway were higher compared to untreated fibroblasts while the difference was less pronounced in STAT3-HIES compared to healthy fibroblasts. Particularly, VEGFA expression in STAT3-HIES fibroblasts was significantly lower compared to healthy individuals, while IL-17 and TGF-beta increased VEGFA expression in fibroblasts of healthy subjects.
The impaired Hif1-alpha and VEGFA response to S. aureus in STAT3-HIES fibroblasts indicates impairments in the hypoxic response and angiogenesis during infection. The impact of IL-17 and TGF-beta on Hif1-alpha and VEGFA in STAT3-HIES fibroblasts, as well as the clinical correlation are currently under further investigation.