IFI204 in microglia mediates traumatic brain injury-induced mitochondrial dysfunction and pyroptosis via SENP7 interaction.

Objectives: Traumatic brain injury (TBI) is a primary contributor to chronic functional impairment in human populations, initiating complex neuroinflammatory cascades and neurodegeneration. Despite extensive research efforts, the precise pathophysiological pathways remain incompletely characterized. This investigation aims to establish a novel therapeutic strategy that targets critical molecular pathways post-injury, potentially addressing the current limitations in the clinical management of TBI patients.

Methods: The single-cell data of cortical tissue from mice with TBI were obtained from public databases (GSE160763), which was utilized to identify alterations in in the composition of disease-associated cells and related molecules as the disease progresses. Functional and pathway enrichment analyses were conducted to elucidate the functional characteristics of microglia and astrocyte subpopulations. Trajectory analysis was employed to investigate cell differentiation characteristics. Subsequently, we examined the expression and function of microglia-specific molecules, such as IFI204, along with their underlying molecular mechanisms using Western blotting, immunofluorescence, co-immunoprecipitation (CO-IP), histopathology, behavioral tests, and molecular docking to assess binding status, as well as molecular dynamics simulations. Finally, we used molecular docking technology to find small molecule compounds that IFI204 can stably bind to.

Results: We identified nine major cell populations, most of which undergo dynamic changes following TBI. Astrocytes and microglia were the predominant populations in each group, and further cluster analysis revealed that the proportions of interferon (IFN) and axonogenesis-related microglial subtypes increased after TBI. Trajectory inference analysis indicated that the expression of Ifi204 is upregulated in microglia during disease progression. Conditional microglial knockdown of IFI204 significantly improved neurological deficits in mice, and alleviated mitochondrial dysfunction and microglial pyroptosis. Mechanistically, SENP7, identified as a novel molecule, interacts with IFI204 in microglia, catalyzes the deSUMOylation of IFI204, and promotes STING signal activation, ultimately driving microglial pyroptosis and mitochondrial dysfunction.

Conclusions: The interaction between IFI204 and SENP7 promotes microglial pyroptosis and related mitochondrial dysfunction. Furthermore, in the case of TBI, we hypothesize that targeting IFI204 might yield therapeutic benefits.