BackgroundTreatment of brain tumors, epilepsy, or hemodynamic abnormalities requires a craniotomy to access the brain. Nearly 1 million craniotomies are performed in the US annually, which increase to ~ 14 million worldwide and despite prophylaxis, infectious complications after craniotomy range from 1 to 3%. Approximately half are caused byStaphylococcus aureus(S. aureus), which forms a biofilm on the bone flap that is recalcitrant to antibiotics and immune-mediated clearance. However, the mechanisms responsible for the persistence of craniotomy infection remain largely unknown. The current study examined the role of IL-10 in promoting bacterial survival.MethodsA mouse model ofS. aureuscraniotomy infection was used with wild type (WT), IL-10 knockout (KO), and IL-10 conditional KO mice where IL-10 was absent in microglia and monocytes/macrophages (CX3CR1CreIL-10fl/fl) or neutrophils and granulocytic myeloid-derived suppressor cells (G-MDSCs;Mrp8CreIL-10fl/fl), the major immune cell populations in the infected brain vs. subcutaneous galea, respectively. Mice were examined at various intervals post-infection to quantify bacterial burden, leukocyte recruitment, and inflammatory mediator production in the brain and galea to assess the role of IL-10 in craniotomy persistence. In addition, the role of G-MDSC-derived IL-10 on neutrophil activity was examined.ResultsGranulocytes (neutrophils and G-MDSCs) were the major producers of IL-10 during craniotomy infection. Bacterial burden was significantly reduced in IL-10 KO mice in the brain and galea at day 14 post-infection compared to WT animals, concomitant with increased CD4+and γδ T cell recruitment and cytokine/chemokine production, indicative of a heightened proinflammatory response.S. aureusburden was reduced inMrp8CreIL-10fl/flbut notCX3CR1CreIL-10fl/flmice that was reversed following treatment with exogenous IL-10, suggesting that granulocyte-derived IL-10 was important for promotingS. aureuscraniotomy infection. This was likely due, in part, to IL-10 production by G-MDSCs that inhibited neutrophil bactericidal activity and TNF production.ConclusionCollectively, these findings reveal a novel role for granulocyte-derived IL-10 in suppressingS. aureusclearance during craniotomy infection, which is one mechanism to account for biofilm persistence.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12974-023-02798-7.