RESUMO
Pyroptosis, a typical inflammatory cell death mode, has been increasingly demonstrated to have therapeutic value in inflammatory diseases such as sepsis. However, the mechanisms and therapeutic targets of sepsis remain elusive. Here, we reported that REGγ inhibition promoted pyroptosis by regulating members of the gasdermin family in macrophages. Mechanistically, REGγ directly degraded Bim, a factor of the Bcl-2 family that can inhibit the cleavage of GSDMD/E, ultimately preventing the occurrence of pyroptosis. Furthermore, cecal ligation and puncture (CLP)-induced sepsis model mice showed downregulation of REGγ at both the RNA and protein levels. Gasdermin-mediated pyroptosis was augmented in REGγ-knockout mice, and these mice exhibited more severe sepsis-related tissue injury. More importantly, we found that REGγ expression was downregulated in clinical sepsis samples, such as those from patients with Pseudomonas aeruginosa (PA) infection. Finally, PA-infected mice showed decreased REGγ levels in the lung. In summary, our study reveals that the REGγ-Bim-GSDMD/E pathway is a novel regulatory mechanism of pyroptosis in sepsis-related tissue injury.
Assuntos
Proteína 11 Semelhante a Bcl-2 , Macrófagos , Camundongos Knockout , Piroptose , Sepse , Animais , Sepse/metabolismo , Sepse/patologia , Macrófagos/metabolismo , Camundongos , Humanos , Proteína 11 Semelhante a Bcl-2/metabolismo , Proteína 11 Semelhante a Bcl-2/genética , Proteínas de Ligação a Fosfato/metabolismo , Camundongos Endogâmicos C57BL , Ubiquitina/metabolismo , Masculino , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteólise , Células RAW 264.7 , Infecções por Pseudomonas/metabolismo , Infecções por Pseudomonas/patologia , Pseudomonas aeruginosa/patogenicidade , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Gasderminas , Autoantígenos , Complexo de Endopeptidases do ProteassomaRESUMO
Chondrosarcoma (CHS) is a malignant bone tumor with insensitivity to both radiotherapy and chemotherapy, and a high recurrence rate. However, the latent mechanism of recurrent CHS (Re-CHS) remains elusive. Here, we discovered that FBXO22 was highly expressed in clinical samples of Re-CHS. FBXO22 played a significant role in various cancers. However, the role of FBXO22 in Re-CHS remained unclear. Our research demonstrated that suppressing FBXO22 abated the proliferation and migration of CHS cells and facilitated their apoptosis. In addition, suppressing FBXO22 raised the expression of PD-L1 in Re-CHS. All these findings provide new evidence for using FBXO22 and PD-L1 as combined targets to prevent and treat Re-CHS, which may prove to be a novel strategy for immunotherapy of CHS, especially Re-CHS.