RESUMO
Autoimmune skin disease is a kind of heterogeneous disease with complicated pathogenesis. Many factors such as genetic, infectious, environmental and even psychological factors may interact together to trigger a synergistic effect for the development of abnormal innate and adaptive immune responses. Although the exact mechanisms remain unclear, recent evidence suggests that pyroptosis plays a pivotal role in the development of autoimmune skin disease. The feature of pyroptosis is the first formation of pores in cellular membranes, then cell rupture and the release of intracellular substances and pro-inflammatory cytokines, such as interleukin-1 beta (IL-1ß) and IL-18. This hyperactive inflammatory programmed cell death damages the homeostasis of the immune system and advances autoimmunity. This review briefly summarises the molecular regulatory mechanisms of pyrin domain-containing protein 3 (NLRP3) inflammasome and gasdermin family, as well as the molecular mechanisms of pyroptosis, highlights the latest progress of pyroptosis in autoimmune skin disease, including systemic lupus erythematosus, psoriasis, atopic dermatitis and systemic scleroderma and attempts to identify its potential advantages as a therapeutic target or prognostic biomarker for these diseases.
Assuntos
Doenças Autoimunes , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Humanos , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Dermatopatias/imunologia , Animais , Proteínas de Ligação a Fosfato/metabolismo , Interleucina-1beta/metabolismo , Escleroderma Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Psoríase/imunologia , Psoríase/metabolismo , Autoimunidade , Interleucina-18/metabolismo , Dermatite Atópica/imunologiaRESUMO
BACKGROUND: Psoriasis is a prevalent chronic inflammatory dermatosis characterized by excessive proliferation of keratinocytes. Protein lysine 2-hydroxyisobutyrylation (Khib) is a newly identified post-translational modification that regulates various biological processes. Abnormal Khib modification has been closely associated with the development of autoimmune diseases. OBJECTIVE: To investigate the abnormal Khib profile and its pathogenic role in psoriasis. METHODS: We utilized liquid chromatography-tandem mass spectrometry to analyze Khib-modified proteins in the epidermis of psoriasis and healthy controls. Mutated cells and mice with downregulated Ebp1Khib210 were generated to investigate its functional effects in psoriasis. RESULTS: The omic analysis revealed dysregulation of Khib modification in psoriatic lesions, exhibiting a distinct profile compared to controls. We observed the downregulation of Ebp1Khib210 in psoriatic lesions and IMQ-induced psoriatic mice. Notably, the expression of Ebp1Khib210 was upregulated in psoriatic patients following effective treatment. Decreased Ebp1Khib210 enhanced keratinocyte viability, proliferation, and survival while inhibiting apoptosis in vitro. Additionally, Pa2g4K210A mice with downregulated Ebp1Khib210 exhibited more severe psoriatic lesions and enhanced keratinocyte proliferation. Moreover, we found that Ebp1K210A mutation increased the interaction between Ebp1 and nuclear Akt, thereby inhibiting MDM2-mediated TIF-IA ubiquitination, and resulting to increased rRNA synthesis and keratinocyte proliferation. The downregulation of Ebp1Khib210 was attributed to inflammation-induced increases in HDAC2 expression. CONCLUSION: Our findings demonstrate that downregulation of Ebp1Khib210 promotes keratinocyte proliferation through modulation of Akt signaling and TIF-IA-mediated rRNA synthesis. These insights into Khib modification provide a better understanding of the pathogenesis of psoriasis and suggest potential therapeutic targets.