IL-10 production by granulocytes promotes Staphylococcus aureus craniotomy infection

Abstract

Background Treatment 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 by Staphylococcus 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. Methods A mouse model of S. aureus craniotomy 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-10 fl/fl) or neutrophils and granulocytic myeloid-derived suppressor cells (G-MDSCs; Mrp8CreIL-10 fl/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. Results Granulocytes (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. aureus burden was reduced in Mrp8CreIL-10 fl/fl but not CX3CR1CreIL-10 fl/fl mice that was reversed following treatment with exogenous IL-10, suggesting that granulocyte-derived IL-10 was important for promoting S. aureus craniotomy infection. This was likely due, in part, to IL-10 production by G-MDSCs that inhibited neutrophil bactericidal activity and TNF production. Conclusion Collectively, these findings reveal a novel role for granulocyte-derived IL-10 in suppressing S. aureus clearance during craniotomy infection, which is one mechanism to account for biofilm persistence.

Metabolism Shapes Immune Responses to <i>Staphylococcus aureus</i>

“…In addition, the large bacterial biomass associated with biofilm elicits continued proinflammatory mediator release, which would perpetuate the G-MDSC inhibitory loop. Another contributing factor is the induction of a robust IL-10 response during S. aureus biofilm infection that promotes infection persistence [ 93 , 99 ]. Therefore, a better understanding of how leukocytes are seemingly refractory to the antimicrobial actions of proinflammatory cytokine stimulation during S. aureus biofilm infection may help to “flip the switch” to reprogram cells for enhanced bactericidal activity [ 120 ].…”

“…In general, G-MDSCs exert their suppressive activity through ROS and arginase 1 (Arg-1), whereas M-MDSCs use iNOS and anti-inflammatory cytokines such as IL-10 and TGF-β to inhibit T cell responses [86][87][88]. G-MDSCs play a pathological role in mouse models of S. aureus infection by inhibiting proinflammatory responses, leading to increased bacterial survival [21, [89][90][91][92][93] and G-MDSCs have also been shown to accumulate at the site of prosthetic joint infection (PJI) in humans [94]. A recent study reported that glycolysis was important for driving G-MDSC maturation into PMNs in a mouse model of systemic S. aureus infection, although this had no effect on bacterial burden [95].…”