Abstract
Patients with severe chronic graft-versus-host disease (cGVHD) always experience debilitating tissue injury and have poorer quality of life and shorter survival time. The early stage of cGVHD is characterized by inflammation, which eventually leads to extensive tissue fibrosis in various organs, such as skin and lung, eventually inducing scleroderma-like changes and bronchiolitis obliterans syndrome. Here we review the functions of serum/glucocorticoid regulated kinase 1 (SGK1), a hub molecule in multiple signal transduction pathways and cell phosphorylation cascades, which has important roles in cell proliferation and ion channel regulation, and its relevance in cGVHD. SGK1 phosphorylates the ubiquitin ligase, NEDD4, and induces Th cells to differentiate into Th17 and Th2 phenotypes, hinders Treg development, and promotes inflammatory fibrosis. Phosphorylation of NEDD4 by SGK1 also leads to up-regulation of the transcription factor SMAD2/3, thereby amplifying the fibrosis-promoting effect of TGF-β. SGK1 also up-regulates the inflammatory transcription factor, nuclear factor-κB (NF-κB), which in turn stimulates the expression of multiple inflammatory mediators, including connective tissue growth factor. Overexpression of SGK1 has been observed in various fibrotic diseases, including pulmonary fibrosis, diabetic renal fibrosis, liver cirrhosis, hypertensive cardiac fibrosis, peritoneal fibrosis, and Crohn’s disease. In addition, SGK1 inhibitors can attenuate, or even reverse, the effect of fibrosis, and may be used to treat inflammatory conditions and/or fibrotic diseases, such as cGVHD, in the future.
Highlights
With the increasing clinical application of haploidentical hematopoietic stem cell transplantation, the incidence of chronic graft-versus-host disease is increasing annually
The early stage of chronic graft-versus-host disease (cGVHD) is characterized by inflammation, which leads to extensive tissue fibrosis and even severe disability [2]
More than 20% of patients with cGVHD will experience sclerosis, which is characterized by thickening of the skin, or fasciitis caused by collagen deposition and fibrosis [4, 5]
Summary
With the increasing clinical application of haploidentical hematopoietic stem cell transplantation, the incidence of chronic graft-versus-host disease (cGVHD) is increasing annually. Th17 cells and an activated Th17-prone, CD146-expressing, CD4+ T-cell subset participate in the development of cGVHD in the BO mouse model [21]. Granulocyte colony-stimulating factor (G-CSF)-mobilized donor grafts cause murine cGVHD with prominent scleroderma and high levels of Th17 cells, which recruit macrophages and produce higher level of profibrotic TGF-b, which are essential for lung and skin fibrosis [24, 25].
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