Role of LIGHT in the Inflammatory Mechanisms of Psoriasis via Upregulation of Proliferation and Cytokine Production of Keratinocytes

TL;DR

This study explores how LIGHT, a protein involved in immune responses, contributes to psoriasis by increasing keratinocyte proliferation and inflammation, suggesting a new treatment target.

Contribution

The study identifies the JNK/AP-1-HVEM-LIGHT pathway as a novel therapeutic target for psoriasis.

Findings

LIGHT treatment increased NF-κB nuclear translocation and pro-inflammatory protein expression in keratinocytes.

Blocking LIGHT receptors or inhibiting NF-κB and JNK/AP-1 reduced inflammation and cell viability.

The JNK/AP-1-HVEM-LIGHT pathway is linked to keratinocyte viability and inflammatory factor production.

Abstract

The pathogenesis of psoriasis is associated with abnormalities in immune pathways. HVEM is known as a receptor of LIGHT (homologous to lymphotoxins, inducible, and competes with HSV glycoprotein D), which is a newly identified member of the TNF superfamily. The expression of HVEM and LTBR (another LIGHT receptor) has been found to be increased in the skin of psoriasis patients. This indicates the potential role of LIGHT and its receptors in the pathogenesis of psoriasis. Therefore, the objective of this study was to examine the effect of LIGHT on keratinocyte proliferation and its therapeutic potential in the treatment of psoriasis.

We used immunohistochemistry to examine their expression in psoriasis‐affected and normal tissue samples. We treated cells of the keratinocyte cell line HaCat with LIGHT protein, anti‐HVEM and anti‐LTβR antibodies, HVEM interference and LTβR interference RNA vectors, and NF‐κB and JNK/AP‐1 inhibitors at various concentrations and for various times, separately or simultaneously. The expression of NF‐κB was examined by immunofluorescence staining, and the expression of inflammatory proteins was measured with ELISA. Further, the viability of HaCat cells was examined with a CCK‐8 kit. In addition, flow cytometry was used to detect the expression of HVEM and LTBR on HaCat cells.

We found that LIGHT treatment of HaCat cells promoted the nuclear translocation of NF‐κB. Further, the expression of p‐c‐Jun, IL‐6, IL‐8, PGI2, and PTGS2 was increased in response to LIGHT treatment, but the expression of these factors was decreased when the LIGHT receptors were blocked or NF‐κB and JNK/AP‐1 expression was inhibited. We also found that the viability of HaCat cells was consistent with the expression of pro‐inflammatory factors.

The present findings indicate that the JNK/AP‐1‐HVEM‐LIGHT pathway played a role in the viability of human keratinocytes and the expression of IL‐6, IL‐8, PGI2, and PTGS2. Thus, the JNK/AP‐1‐HVEM‐LIGHT pathway might be a potential target for the treatment of psoriasis.

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