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 5

Analysis of HIF-1α expression, vascularization, and ECM composition in skin wounds and coronary arteries of AD-HIES patients.

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Analysis of HIF-1α expression, vascularization, and ECM composition in s...
(A) Decreased HIF-1α expression in granulation tissue during skin-wound healing of AD-HIES patients. Immunostaining of skin biopsy sections 7 days after initial biopsy. See Figure 1 for experiment details. Left: representative images. Scale bars: 50 μm. Right: quantification (see Methods) (n = 3). (B) Decreased HIF-1α expression in coronary arteries of AD-HIES patients. Immunostaining for HIF-1α protein. Scale bars: 500 μm. (C) Decreased levels of MMP1 and MMP3 mRNA in AD-HIES coronary arteries (in situ hybridization RNAscope assay). Top: representative images. Bottom: Quantification of MMP1 (n = 6 [control], n = 4 [AD-HIES]), and MMP3 (n = 9 [control], n = 5 [AD-HIES]) mRNA expression. Scale bars: 10 μm. See Supplemental Figure 11B for more images. (D) Decreased vasa vasorum perfusion in CA in adventitia. Left: representative images of CA sections stained for CD31 to identify vasa vasorum (black arrows). Scale bars: 100 μm. Right: image quantification: number of vasa vasorum vessels per mm2 of adventitia and blood perfusion presented as percentages of adventitia area occupied by vasa vasorum (n = 10 [control], n = 5 [AD-HIES]). (E) Increased elastic fibers (black) in adventitia of AD-HIES arteries. (F) Analysis of individual components of ECM by immunostaining with antibodies for elastin, collagen I, collagen IV, and laminin. Bottom: representative images of stainings. Top: quantification. Intensity of DAB staining is measured in the intima, media, and adventitia. Results presented relative to the average intensity in sections from control coronary arteries (n = 3–8). Scale bars: 100 μm. See also Methods and Supplemental Figure 11A for details of analysis. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, 2-tailed unpaired t test. See Supplemental Table 1 for information about patient samples.