Skin inflammatory diseases like psoriasis (PS) and atopic dermatitis (AD) exhibit some features in common, including a thickened epidermis caused by excessive proliferation of keratinocytes and strong cellular infiltrates into the lesional areas. Despite these similarities, many patients present with distinct immune signatures, with the interleukin-23 (IL-23)/T helper 17 (Th17) axis dominating in PS compared to a predominant Th2 type immune response in many patients with AD [1]. Keratinocytes are a primary skin cell type that are both responsive, and contribute, to the inflammatory environment in both diseases. Keratinocytes can be the source of several autoantigens (e.g., LL37, lipid antigens generated by PLA2) which may trigger T cell activation to initiate PS [2]. Keratinocytes can also secrete select chemokines and cytokines such as CCL17, CCL22, and TSLP to shape the Th2 type immune response in AD [1]. Moreover, the receptors for characteristic cytokines for each disease, such as IL-17, IL-22, and IL-13, that are produced by activated T cells and other immune cells, are expressed on keratinocytes, and they contribute to keratinocyte deregulation, promoting proliferation and production of inflammatory molecules, amplifying cutaneous inflammation and leading to chronicity [[3], [4], [5]]. IL-13 has proven central to AD as shown by clinical responses to therapy with antibodies to IL-4Rα and IL-13 (dupilumab, tralokinumab) [6,7]; and IL-17 is central to PS, shown by therapeutic responses to several IL-23 and IL-17 blockers (ustekinumab, secukinumab, others) [8].

However, whether there are cytokines that might be common drivers of skin inflammation in general, and pivotal to both PS and AD, is only just beginning to be understood. Previously, we reported that animals deficient in TWEAK (TNF superfamily member 12) were protected from experimental PS and AD, and that the TWEAK receptor, Fn14, was expressed on keratinocytes and could act together with IL-17 or IL-13 and lead to enhanced keratinocyte production of inflammatory molecules [9]. This data has then suggested that some cytokines could be common participants in both skin diseases and not associate with for example only Type 2 or only Type 17 immunity. In this regard, we also previously found that another TNF family cytokine, LIGHT (homologous to Lymphotoxin, exhibits Inducible expression and competes with HSV Glycoprotein D for binding to Herpesvirus entry mediator, a receptor expressed on T lymphocytes) also known as Tumor necrosis factor superfamily member 14 (TNFSF14) was required for skin inflammation in mouse models of scleroderma and AD [10,11], and conditional deletion of one of LIGHT's receptors, herpesvirus entry mediator (HVEM), in keratinocytes limited clinical features of AD skin inflammation [11]. LIGHT is primarily produced by activated T cells, either in membrane form or as a soluble cytokine, regardless of whether they are CD4 or CD8 T cells, or their further polarization into T cell subsets. LIGHT also may be products of dendritic cells, monocytes, and granulocytes in some situations [12,13]. This further suggests that LIGHT might be another molecule that through acting on keratinocytes could be pivotal to multiple types of skin disease. However, whether it is central to psoriasis is unknown. Also, whether HVEM is LIGHT's primary receptor is not clear given that LIGHT has another receptor, Lymphotoxin beta receptor (LTβR), that is also expressed on keratinocytes [10].

Here, we report a pathogenic role of LIGHT in a model of PS and that conditional deletion of LTβR or HVEM in keratinocytes equivalently protects against psoriatic skin inflammation. We extend this to a model of AD and show that conditional deletion of LTβR in keratinocytes also protects against allergen-driven skin inflammation. Analysis of publicly available scRNA-seq data from healthy, AD and PS patients found LTβR and HVEM mRNA in keratinocytes, and that LIGHT mRNA is upregulated in T cells from skin lesions of both diseases. Lastly, stimulation of human keratinocytes dominantly expressing LTβR with recombinant LIGHT revealed changes in transcriptional activity of many genes that are known to be elevated in lesional skin from PS and AD patients. Thus, LIGHT interacting with LTβR and HVEM may contribute to keratinocyte dysregulation in PS and AD.