Abstract
Psoriasis is a chronic autoimmune skin disease that can often be triggered upon skin injury, known as Koebner phenomenon. Type 1 interferons (IFNα and IFNβ), key cytokines that activate autoimmunity during viral infection, have been suggested to play an indispensable role in initiating psoriasis during skin injury. Type 1 IFN-inducible gene signature has been identified as one of the major upregulated gene signatures in psoriatic skin. Type 1 IFNs treatments often directly induce or exacerbate psoriasis, whereas blocking type 1 IFNs signaling pathway in animal models effectively inhibits the development of T cell-mediated skin inflammation and psoriasis-like inflammatory diseases. Epidermal keratinocytes (KCs) occupy the outermost position in the skin and are the first responder to skin injury. Skin injury rapidly induces IFNβ from KCs and IFNα from dermal plasmacytoid dendritic cells (pDCs) through distinct mechanisms. Host antimicrobial peptide LL37 potentiates double-stranded RNA (dsRNA) immune pathways in keratinocytes and single-stranded RNA or DNA pathways in pDCs, leading to production of distinct type 1 IFN genes. IFNβ from KC promotes dendritic cell maturation and the subsequent T cell proliferation, contributing to autoimmune activation during skin injury and psoriasis pathogenesis. Accumulating evidences have indicated an important role of this dsRNA immune pathway in psoriasis pathogenesis. Together, this review describes how skin injury induces type 1 IFNs from skin cells and how this may initiate autoimmune cascades that trigger psoriasis. Targeting keratinocytes or type 1 IFNs in combination with T cell therapy may result in more sustainable effect to treat auto-inflammatory skin diseases such as psoriasis.
Highlights
Skin, the largest organ of human body, functions as a physical and immunological barrier to protect our bodies from external threats
Immunostaining analyses have shown that while IFNα is pre-dominantly produced by dermal infiltrated plasmacytoid dendritic cells (pDCs), IFNβ expression is rapidly induced in epidermal keratinocytes as early as 1 day post-wounding and in psoriatic epidermis compared to normal human skin [2, 12, 13]
We have showed that, wounded keratinocytes upregulate the expression of antimicrobial peptide LL37, which enables MAVS and TLR3 in keratinocytes to recognize double-stranded RNA (dsRNA) released from dying cells [2]
Summary
The largest organ of human body, functions as a physical and immunological barrier to protect our bodies from external threats. We review current understanding of immunopathology of psoriasis, the role of keratinocytes in psoriasis initiation, and emphasize on the role of type 1 IFNs in linking innate immune activation upon skin injury and the subsequent autoimmune amplification that leads to psoriasis. New biological drugs against specific immunological elements have gained popularity as safe and effective alternatives to treat moderate to severe plaque psoriasis These biological drugs including monoclonal antibodies against TNFα (such as etanercept and infliximab), IL12 (such as Ustekinumab), IL23 (such as Guselkumab and Tildrakizumab), IL-17A (such as Secukinumab and Ixekizumab), or IL17AR (such as Brodalumab) have shown clinical efficacy in improving skin conditions in clinical trials and most of these drug are already on the market [9, 19,20,21]. An epidermal mechanism is likely to play a role in the development of a Koebner reaction in psoriatic patient
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