Decoy receptor 3 is involved in epidermal keratinocyte commitment to terminal differentiation via EGFR and PKC activation

Decoy receptor 3 (DcR3) is a soluble receptor for Fas ligand, LIGHT and TL1A, but it also exerts effector functions. Previously, we found that DcR3 is upregulated in the serum and lesional skin of patients with psoriasis and is upregulated by EGFR activation in proliferating primary human epidermal keratinocytes. However, the functional role of intracellular DcR3 in keratinocyte differentiation is still incompletely defined. Herein, primary cultured human epidermal keratinocytes were differentiated by phorbol 12-myristate 13-acetate (PMA) treatment, calcium treatment and cell confluence, which are three standard in vitro differentiation models. We found that the constitutive expression of the DcR3 gene and protein was progressively suppressed during terminal differentiation of keratinocytes. These changes were correlated with downregulation of EGFR activation during keratinocyte differentiation. EGFR inhibition by gefitinib further decreased confluence-induced suppression of DcR3 mRNA expression, and, vice versa, knocking down DcR3 expression attenuated EGFR and EGFR ligand expression as well as EGFR activation. Under conditions without a change in cell growth, DcR3 silencing reduced the expression of involucrin and transglutaminase 1 but enhanced the induction of the terminal differentiation markers keratin 10 and loricrin. Of note, DcR3 interacted with PKC alpha and PKC delta and enhanced PKC activity. In keratinocytes with PKC alpha and PKC delta silencing, differentiation markers were differentially affected. In conclusion, DcR3 expression in keratinocytes is regulated by EGFR and forms a positive feedback loop to orchestrate constitutive EGFR and PKC activity. During differentiation, DcR3 is downregulated and involved in modulating the pattern of terminal differentiation. Dermatology: abnormal development of skin cells in psoriasis A protein linked to cancer and various inflammatory diseases may also be an important driver for the skin condition in psoriasis. The outer surface of the skin is formed by cells called keratinocytes, which transition from a highly proliferative state to a fully mature state where they no longer divide. This developmental process is disrupted in psoriasis. Researchers led by Wan-Wan Lin at National Taiwan University, Taipei, have now identified a prominent role for a protein called decoy receptor 3 (DcR3), which is a biomarker for a variety of disorders and is also abnormally expressed in keratinocytes in psoriatic lesions. Lin and colleagues demonstrated that DcR3 interacts with multiple cellular signaling pathways that coordinate cell differentiation. These findings reveal how aberrant DcR3 activity might lead to the abnormal keratinocyte developmental behavior observed in psoriasis.

Automated summary

DcR3 is regulated by EGFR in keratinocytes and involved in modulating the pattern of terminal differentiation. It interacts with PKC to enhance PKC activity. This study reveals the mechanism of how DcR3 regulates abnormal keratinocyte development in psoriasis.