TWEAK/Fn14 Activation Participates in Ro52-Mediated Photosensitization in Cutaneous Lupus Erythematosus
Yale Liu1, Meifeng Xu1, Xiaoyun Min2
1Department of Dermatology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
Abstract:
Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) binds to its sole receptor fibroblast growth factor-inducible 14 (Fn14), participating in various inflammatory responses. Recently, TWEAK/Fn14 activation was found prominent in the lesions of cutaneous lupus erythematosus (CLE). This study was designed to further reveal the potential role of this pathway in Ro52-mediated photosensitization. TWEAK, Fn14, and Ro52 were determined in the skin lesions of patients with CLE. Murine keratinocytes received ultraviolet B (UVB) irradiation or plus TWEAK stimulation and underwent detection for Ro52 and proinflammatory cytokines. The chemotaxis of J774.2 macrophages was evaluated on TWEAK stimulation of cocultured keratinocytes. We found that TWEAK, Fn14, and downstream cytokines were highly expressed in CLE lesions that overexpressed Ro52. Moreover, TWEAK enhanced the UVB-induced Ro52 upregulation in murine keratinocytes. Meanwhile, TWEAK stimulation of keratinocytes favored the migration of macrophages through promoting the production of chemokine C-C motif ligands 17 and 22. Furthermore, Fn14 siRNA transfection or nuclear factor-kappa B (NF-κB) inhibitor abrogated the TWEAK enhancement of Ro52 expression in keratinocytes. Similarly, TNF receptor associated factor 2 (TRAF2) siRNA reduced the protein level of Ro52 in these cells upon TWEAK stimulation. Interestingly, UVB irradiation increased the expression of TNF receptor type 1 (TNFR1) but not affecting TNFR2 expression in keratinocytes. In conclusion, the TWEAK/Fn14 signaling participates in Ro52-mediated photosensitization and involves the activation of NF-κB pathway as well as the function of the TRAF2/TNFR partners.
Insights
The TWEAK/Fn14 pathway is implicated in skin inflammation in cutaneous lupus erythematosus (CLE). This pathway enhances Ro52 expression and promotes macrophage migration, contributing to photosensitization.
Area of Science:
- Immunodermatology
- Molecular biology
- Cellular signaling
Background:
- Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are involved in inflammatory responses.
- TWEAK/Fn14 pathway activation is observed in cutaneous lupus erythematosus (CLE) lesions.
- The role of this pathway in Ro52-mediated photosensitization in CLE requires further investigation.
Purpose of the Study:
- To investigate the role of the TWEAK/Fn14 signaling pathway in Ro52-mediated photosensitization in CLE.
- To determine the expression levels of TWEAK, Fn14, and Ro52 in CLE skin lesions.
- To elucidate the molecular mechanisms underlying TWEAK/Fn14-induced effects on Ro52 expression and macrophage chemotaxis.
Main Methods:
- Analysis of TWEAK, Fn14, and Ro52 expression in CLE skin lesions.
- In vitro studies using murine keratinocytes subjected to ultraviolet B (UVB) irradiation and/or TWEAK stimulation.
- Assessment of Ro52 and proinflammatory cytokine levels in stimulated keratinocytes.
- Evaluation of macrophage chemotaxis using cocultured keratinocytes and J774.2 macrophages.
- Manipulation of Fn14, nuclear factor-kappa B (NF-κB), and TNF receptor associated factor 2 (TRAF2) using siRNA or inhibitors.
Main Results:
- TWEAK, Fn14, and downstream cytokines were highly expressed in CLE lesions with high Ro52 levels.
- TWEAK significantly enhanced UVB-induced Ro52 upregulation in murine keratinocytes.
- TWEAK stimulation of keratinocytes promoted macrophage migration by increasing chemokine (C-C motif) ligand 17 and 22 production.
- Knockdown of Fn14 or inhibition of NF-κB abrogated TWEAK's enhancement of Ro52 expression.
- TRAF2 knockdown reduced Ro52 protein levels upon TWEAK stimulation.
- UVB irradiation increased TNF receptor type 1 (TNFR1) expression in keratinocytes.
Conclusions:
- The TWEAK/Fn14 signaling pathway plays a significant role in Ro52-mediated photosensitization in CLE.
- This pathway involves the activation of the NF-κB signaling cascade.
- TRAF2 and TNFR partners are crucial in mediating the TWEAK-induced effects on Ro52 expression.
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