Impaired angiogenesis and extracellular matrix metabolism in autosomal-dominant hyper-IgE syndrome
Natalia I. Dmitrieva, … , Guibin Chen, Manfred Boehm
Natalia I. Dmitrieva, … , Guibin Chen, Manfred Boehm
Published May 5, 2020
Citation Information: J Clin Invest. 2020;130(8):4167-4181. https://doi.org/10.1172/JCI135490.
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Research Article Vascular biology

Impaired angiogenesis and extracellular matrix metabolism in autosomal-dominant hyper-IgE syndrome

Abstract

There are more than 7000 described rare diseases, most lacking specific treatment. Autosomal-dominant hyper-IgE syndrome (AD-HIES, also known as Job’s syndrome) is caused by mutations in STAT3. These patients present with immunodeficiency accompanied by severe nonimmunological features, including skeletal, connective tissue, and vascular abnormalities, poor postinfection lung healing, and subsequent pulmonary failure. No specific therapies are available for these abnormalities. Here, we investigated underlying mechanisms in order to identify therapeutic targets. Histological analysis of skin wounds demonstrated delayed granulation tissue formation and vascularization during skin-wound healing in AD-HIES patients. Global gene expression analysis in AD-HIES patient skin fibroblasts identified deficiencies in a STAT3-controlled transcriptional network regulating extracellular matrix (ECM) remodeling and angiogenesis, with hypoxia-inducible factor 1α (HIF-1α) being a major contributor. Consistent with this, histological analysis of skin wounds and coronary arteries from AD-HIES patients showed decreased HIF-1α expression and revealed abnormal organization of the ECM and altered formation of the coronary vasa vasorum. Disease modeling using cell culture and mouse models of angiogenesis and wound healing confirmed these predicted deficiencies and demonstrated therapeutic benefit of HIF-1α–stabilizing drugs. The study provides mechanistic insights into AD-HIES pathophysiology and suggests potential treatment options for this rare disease.

Authors

Natalia I. Dmitrieva, Avram D. Walts, Dai Phuong Nguyen, Alex Grubb, Xue Zhang, Xujing Wang, Xianfeng Ping, Hui Jin, Zhen Yu, Zu-Xi Yu, Dan Yang, Robin Schwartzbeck, Clifton L. Dalgard, Beth A. Kozel, Mark D. Levin, Russell H. Knutsen, Delong Liu, Joshua D. Milner, Diego B. López, Michael P. O’Connell, Chyi-Chia Richard Lee, Ian A. Myles, Amy P. Hsu, Alexandra F. Freeman, Steven M. Holland, Guibin Chen, Manfred Boehm

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Figure 6

Pharmacological stabilization of HIF-1α protein increases expression of proangiogenic factors and restores the ability of AD-HIES fibroblasts to support angiogenesis.

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Pharmacological stabilization of HIF-1α protein increases expression of ...
To stabilize HIF-1α, cells were treated with 2 PHD inhibitors: DMF and daprodustat (DD). (A and B) DMF and DD stabilize HIF-1α under regular cell culture conditions, under hypoxia, and in the presence of TNF-α in AD-HIES fibroblasts. (A) Representative Western blot images. (B) Quantification (n = 3–4). (C) DMF increases HIF-1α transcriptional activity in both control and AD-HIES fibroblasts. Luciferase reporter assay with construct containing HRE was performed under basal conditions (n = 8). (D) DMF and DD increase mRNA levels of proangiogenic factors (n = 4–9). (E) DMF and DD increase secretion of proangiogenic factors by AD-HIES fibroblasts (15-hour treatment, n = 11). (F) DMF improves ability of cell culture medium collected from AD-HIES fibroblasts to support angiogenesis in an endothelial cell tube formation assay with VEGFA being a major contributor. To neutralize VEGFA, the cell culture medium was supplemented with bevacizumab (see Methods). Top: representative images of HUVECs taken 9 hours after seeding on Matrigel. Scale bars: 200 μm. Bottom: Quantification of different features of tubule structures (n = 7). Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, 1-way ANOVA followed by Holm-Šidák multiple comparisons test (B and F), 2-tailed unpaired t test in (C), Kruskal-Wallis test followed by Dunn’s multiple comparisons test (D and E). See Supplemental Table 1 for information about patient samples used.