Gasdermin E promotes translocation of p65 and c-jun into nucleus in keratinocytes for progression of psoriatic skin inflammation.

Gasdermin E (GSDME) has recently been identified as a critical executioner to mediate pyroptosis. While epidermal keratinocytes can initiate GSDME-mediated pyroptosis, the role of keratinocyte GSDME in psoriatic dermatitis remains poorly characterized. Through analysis of GEO datasets, we found elevated GSDME levels in psoriatic lesional skin. Additionally, GSDME levels correlated with both psoriasis severity and response to biologics treatments. Single-cell RNA sequencing (scRNA-seq) from a GEO dataset revealed GSDME upregulation in keratinocytes of psoriasis patients. In the imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model, both full-length and cleaved forms of caspase-3 and GSDME were elevated in the epidermis. Abnormal proliferation and differentiation of keratinocytes and dermatitis were attenuated in Gsdme-/- mice and keratinocyte-specific Gsdme conditional knockout mice after IMQ stimulation. Exposure of keratinocytes to mixed cytokines (M5), mimicking psoriatic conditions, led to GSDME cleavage. Moreover, the interaction between GSDME-FL and p65 or c-jun was significantly increased after M5 stimulation. GSDME knockdown inhibited nuclear translocation of p65 and c-jun and decreased upregulation of psoriatic inflammatory mediators such as IL1ß, CCL20, CXCL1, CXCL8, S100A8, and S100A9 in M5-challenged keratinocytes. In conclusion, GSDME in keratinocytes contributes to the pathogenesis and progression of psoriasis, potentially in a pyroptosis-independent manner by interacting and promoting translocation of p65 and c-jun. These findings suggest that keratinocyte GSDME could serve as a potential therapeutic target for psoriasis treatment.

Reduction of miR-133a-3p contributes to apoptosis and gasdermin E-mediated pyroptosis of keratinocytes in skin exposed to ultraviolet B radiation.

Engagement of regulated cell death in keratinocytes plays a crucial role in the pathogenesis and development of skin disorders associated with UV radiation. However, it remains unclear how microRNAs (miRNAs) participate in the regulation of UV-caused keratinocyte death. In this study, we found that miR-133a-3p was decreased in the epidermis of UVB-challenged mice and UVB-irradiated keratinocyte cell line HaCaT cells. The intradermal injection of agomir miR-133a-3p ameliorated skin damage of UVB-challenged mice, especially epidermal necrosis. Meanwhile, the injection inhibited apoptosis indicator PARP cleavage and pyroptosis indicator GSDME cleavage in the epidermis. In UVB-challenged HaCaT cells, transfection of miR-133a-3p mimic or inhibitor alleviated or aggravated UVB-induced apoptosis and GSDME-mediated pyroptosis respectively. miR-133a-3p was also involved in the effects of metformin treatment on alleviating skin damage in UVB-challenged mice and on inhibiting apoptosis and GSDME-mediated pyroptosis in UVB-irradiated HaCaT cells. We confirmed that CYLD is a target gene of miR-133a-3p and participates in the protective effects of miR-133a-3p on inhibiting UVB-caused apoptosis and GSDME-mediated pyroptosis in keratinocytes. This study indicates a pivotal role for miR-133a-3p of keratinocytes in UVB-caused skin damage. Alleviating skin photodamage by restoring the decrease of miR-133a-3p can be considered a potential therapeutic approach.

Necroptosis-mediated HMGB1 secretion of keratinocytes as a key step for inflammation development in contact hypersensitivity.

Keratinocyte necroptosis (with proinflammatory characteristic) is required for epidermal damage in contact hypersensitivity (CHS). In DNCB-induced CHS mice model, we observed the aggravated keratinocyte death and increased phosphorylation level of MLKL, RIPK3 and RIPK1. However, CHS skin lesion did not present in keratinocyte-specific Mlkl knockout mice. We validated that MLKL-mediated keratinocyte necroptosis is required for epidermal damage in response to immune microenvironment in CHS. Moreover, MLKL-mediated necroptosis deficiency or inhibition resulted in blocking recruitment and activation of inflammatory cells in CHS via reducing HMGB1 release in keratinocytes. This study suggests that MLKL-mediated keratinocyte necroptosis functions as a self-amplified actor in inflammatory responses and could be considered as an effective therapeutic target. It proposes an innovative prospective that inhibiting keratinocyte necroptosis can prevent the development of epidermal damage in CHS.