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 Therapeutics 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 1

Delayed skin-wound healing in AD-HIES patients after tissue injury.

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Delayed skin-wound healing in AD-HIES patients after tissue injury. (A) ...
(A) Overview of human cutaneous wound-healing model. A skin defect was created using a 2-mm-diameter skin punch biopsy tool (2 mm core biopsy of skin is excised to the depth of the deep dermis/dermal subcutaneous junction). Three or 7 days after the initial biopsy, a 3-mm skin punch biopsy of skin surrounding the original punch biopsy site was performed and the wound-healing process analyzed by Masson’s trichrome and immunohistochemistry. Upper: representative images of wounds at days 3 and 7. Lower: representative images of perpendicularly bisected biopsies. Dark blue staining indicates abundant collagen. Red color indicates early granulation tissue (GT) with much less collagen (asterisks). (See also Supplemental Figure 1, A and B.) (B–E) Delayed GT formation, collagen restoration, and vascularization during skin-wound healing in AD-HIES patients. Three AD-HIES patients and 3 matched controls were analyzed. (B) At day 7, AD-HIES sections contain larger areas of less mature GT that lacks collagen. Data are plotted as percentages of biopsy section area occupied by GT with no or low collagen (n = 3). See also Supplemental Figure 1, C and D. (C) AD-HIES fibroblasts generate less collagen at day 7 after injury. Representative Masson’s trichrome stain of GT (magnification of area labeled with asterisk in A). Scale bars: 50 μm. Collagen fibers show dark blue staining in the control, but weak to minimal staining in AD-HIES skin. (D) Decreased efficiency of new blood vessel formation in GT of AD-HIES. Representative images of staining for CD31 (a vascular endothelial cell marker) showed decreased vascularity and decreased endothelial cell staining in dermis. Scale bars: 1 mm. (E) Impaired vascularization and STAT3 signaling in GT of AD-HIES patients. Left: representative images of staining for CD31, STAT3, and p-STAT3. Scale bars: 50 μm. Locations of the images are indicated by asterisks in A. Right: Quantification of the images (see Methods for details) (n = 3). Decreased CD31 content indicates deficient angiogenesis during wound healing. While almost all cells in GT express STAT3 protein both in control and in AD-HIES, percentages of cells that express p-STAT3 are greatly reduced in AD-HIES. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01, 2-tailed unpaired t test (B and E). See also Supplemental Figure 1. See Supplemental Table 1 for information about patient samples used.