MYSM1-mediated epigenetic modification dysregulation leads to immunosuppression and secondary infections in sepsis

Authors:
Open Access
Publisher website
Google Scholar
Abstract
Sepsis is a life-threatening condition characterized by a dysregulated immune response to infection, often leading to organ dysfunction and even death. During the recovery phase of sepsis, patients frequently exhibit impaired antimicrobial function of immune cells, which exacerbates the state of immunosuppression and increases the risk of secondary infections. However, therapeutic strategies targeting sepsis-induced immunosuppression have yet to achieve breakthrough progress, with the core challenge lying in the significant gaps in understanding the molecular mechanisms underlying immunosuppression. In this study, we integrated clinical samples, mouse models, and molecular mechanisms to reveal that the reduction in macrophage function and epigenetic dysregulation, particularly histone ubiquitination, are central drivers of sepsis-induced immunosuppression. Further investigation demonstrated that MYSM1, a deubiquitinase, plays a pivotal role in regulating this ubiquitination process. Targeted deletion of the N-terminal domain of MYSM1 markedly enhances the inflammatory response during the early phase of secondary infection in sepsis, facilitating bacterial clearance and significantly mitigating tissue damage in the late phase of secondary infection, thereby improving the survival outcomes in mice. Overall, our study elucidates the role of MYSM1-mediated dysregulation of epigenetic modifications in the immune response during the late phase of sepsis, providing a novel therapeutic approach for addressing sepsis-related immune dysfunction.
Funding Information
  • Hubei Provincial Key Research and Development Program (2023BCB017)
  • National Key R&D Program Special Project on Technology Response to Active Health and Population Aging (2023YFC3604700)
  • National Key R&D Program Special Project on Diagnostic and Therapeutic Equipment and Biomedical Technology (2022YFC2401900)
  • National Natural Science Foundation of China (32400131)

This publication has 57 references indexed in Scilit: