RESUMEN
Psoriasis is a highly prevalent chronic disease associated with a substantial social and economic burden. Oxeiptosis is a programmed cell death that occurs when cells are in a state of high oxidative stress, which has a potent anti-inflammatory effect. However, there is still no research on oxeiptosis in psoriasis, and the agonists or antagonists of oxeiptosis remain an unclear field. Here, we found that oxeiptosis of keratinocytes was inhibited in psoriasis lesions. KEAP1, as the upstream molecular component of oxeiptosis, is highly expressed in psoriasis lesions. Knockdown of KEAP1 in HaCaT cells caused oxeiptosis in the condition of M5 cocktail stimulation. Next, we found that the cell-permeable derivative of itaconate, 4-octylitaconate (OI) promoted oxeiptosis of keratinocytes by inhibiting KEAP1 and then activating PGAM5 which are two upstream molecular components of oxeiptosis. At the same time, OI can reduce the expression of inflammatory cytokines induced by M5 cocktail stimulation in vitro. Similarly, we found that OI can alleviate IMQ-induced psoriatic lesions in mice and downregulate the levels of inflammatory cytokines in psoriatic lesions. In summary, our findings suggest that oxeiptosis of keratinocytes was inhibited in psoriasis and OI can significantly inhibit inflammation and alleviate psoriasis as an agonist of oxeiptosis, indicating that oxeiptosis may be involved in regulating the progression of psoriasis, which may provide new therapeutic targets for psoriasis treatment.
Asunto(s)
Factor 2 Relacionado con NF-E2 , Psoriasis , Humanos , Animales , Ratones , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Psoriasis/inducido químicamente , Inflamación/tratamiento farmacológico , Queratinocitos , Citocinas/metabolismoRESUMEN
A wide spectrum of metabolites (mainly, the three major nutrients and their derivatives) can be sensed by specific sensors, then trigger a series of signal transduction pathways and affect the expression levels of genes in epigenetics, which is called metabolite sensing. Life body regulates metabolism, immunity, and inflammation by metabolite sensing, coordinating the pathophysiology of the host to achieve balance with the external environment. Metabolic reprogramming in cancers cause different phenotypic characteristics of cancer cell from normal cell, including cell proliferation, migration, invasion, angiogenesis, etc. Metabolic disorders in cancer cells further create a microenvironment including many kinds of oncometabolites that are conducive to the growth of cancer, thus forming a vicious circle. At the same time, exogenous metabolites can also affect the biological behavior of tumors. Here, we discuss the metabolite sensing mechanisms of the three major nutrients and their derivatives, as well as their abnormalities in the development of various cancers, and discuss the potential therapeutic targets based on metabolite-sensing signaling pathways to prevent the progression of cancer.
Asunto(s)
Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Transducción de Señal , Metabolismo Energético , Epigénesis Genética , Microambiente TumoralRESUMEN
Psoriasis is an autoimmune chronic inflammatory skin disease with an unclear pathogenesis that is difficult to cure, causing serious physical and mental burdens for patients. Previous research showed that a mutually reinforcing vicious cycle caused by keratinocytes (KC) and a variety of immune cells plays an important role in psoriatic inflammation. d-Mannose, a widely distributed metabolite in the body, has been found to treat several metabolic diseases, but its impact on psoriasis remains unknown. Our study aims to investigate the effects of d-mannose on psoriasis and its specific mechanism. Here, we found that d-mannose alleviates psoriasis in mice both as oral and topical agents. Specifically, d-mannose down-regulated the expression of hypoxia-inducible factor 1A(HIF-1α) and inhibited the expression of chemokine CCL20 in keratinocytes, thereby inhibiting the local infiltration of Th17 cells and breaking the cycle of keratinocytes-Th17 cells. Overall, our study indicates that d-mannose alleviates cutaneous inflammation in psoriasis by inhibiting the HIF-1α/CCL20/Th17 cells axis, and d-mannose has the potential to be used as an oral and topical agent in the treatment of psoriasis.