Received January 21, 2016; Accepted July 09, 2016; Published August 30, 2016
http://dx.doi.org/10.18081/2333-5106/016-276-288
Sascha Vierkotten; Victoria Korinek; Philip Frugier
Abstract
Heterodimeric TGF-β, a key regulator in epithelium homeostasis, influences proliferation, apoptosis, migration, or differentiation. Its aberrant signaling triggers disorders like cancer, fibrosis, or autoimmune disease. Versatile roles of TGF-β in immune response modulation affect Th1/Th2 polarization during Th activation. This dual function results in active discrimination between sites of ocular immunogenic inflammation and the non-inflammatory immune privileged state. Uveitis comprises a spectrum of ocular inflammatory disease with an assortment of pathogenic mechanisms and environmental exposures. The induction of uveitis depends on porcine retinal S-antigen (S-Ag). The TGF-β pathway facilitates the immunogenicity of S-Ag. Homotetrameric and heterotrimeric forms of TGF-β 1-3 were initially produced via E. coli expression systems. Heterodimeric TGF-β1/2 and TGF-β1/3 transformed porcine retinal pigment epithelium cells. The siRNA-mediated TGF-β1/3 targeting. HTRA1 provoked TGF-β isoform upregulation. Uncovering a novel immune-polarizing role of human HTRA1 in TGF-β responsiveness shift provides new insights into the pathogenesis of uveitis. HTRA1 is a secreted serine protease belonging to the high-temperature requirement serine protease (HTRA) family. The intriguing biological roles of HTRA1 regulate biological processes, including apoptosis, cell growth, inflammation, and proteotoxicity. Pathogenic mutations or polymorphisms in the regulatory region conveying altered expression of HTRA1 have been linked to human diseases including age-related macular degeneration (AMD)/polypoidal choroidal vasculopathy (PCV) and diabetic retinopathy (DR). HTRA1 aberrant upregulation contributes to retinal pigment epithelium dysregulation and subsequent retinal degeneration via modifying various signaling pathways. The results presented in this work elucidate the role of HTRA1 in altering the TGF-β signaling pathway in the context of the host cell cytokine milieu, thereby enhancing the uveitis signaling cascade and revealing the underlying mechanisms. Through delineating a dual pathway in the TGF-β cascade, these findings extend the understanding of the HTRA1 role in uveitis pathogenesis and provide new insights into uveitis therapy.
Key words: HtrA1; Uveitis; Proinflammatory cytokines; TGF-β
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