TRIM28 SUMOylates IRF3 in astrocytes to drive neutrophils infiltration and ischemic cerebral injury.

Crosstalk between the nervous and immune systems is responsible for ischemic cerebral injury. However, the molecular mechanism and regulatory network underlying this interaction still have not been completely illuminated. In this study, we found that the E3 SUMOylase Tripartite Motif-Containing Protein 28 (TRIM28) was primarily upregulated in astrocytes after ischemic stroke (IS), and elevated plasma TRIM28 levels correlated with poor prognosis in IS patients. Astrocyte-specific Trim28 knockout relieved IS-mediated cerebral injury. Conversely, in astrocyte-specific Trim28 knockout mice, AAV-mediated re-expression of TRIM28 in astrocytes aggravated IS-mediated neuroinflammation and cerebral injury. Mechanistically, TRIM28 catalyzed SUMO1 conjugation of interferon regulatory factor 3 (IRF3) at lysine 77, which stabilized intranuclear IRF3 by inhibiting K48-linked ubiquitination and subsequent proteasomal degradation. Stabilized IRF3 transcriptionally upregulated C-X-C motif chemokine ligand 1 (CXCL1), thereby enhancing CXCL1-CXCR2 signaling to promote CXCR2+ neutrophils chemotaxis and infiltration into the ischemic brain. Importantly, virtual screening of the FDA-approved drug library identified Acarbose as a pharmacological inhibitor of TRIM28-IRF3 axis, and Acarbose administration relieved neutrophils brain infiltration and cerebral injury after IS. Our findings highlight the critical role of TRIM28 in regulating crosstalk between astrocytes and neutrophils and nominate TRIM28 as a tractable therapeutic target for ischemic cerebral injury.