title: IL-12 promotes myeloid-derived suppressor cell recruitment and bacterial persistence during Staphylococcus aureus orthopedic implant infection.
abstract: Staphylococcus aureus is a leading cause of human prosthetic joint infections (PJIs) typified by biofilm formation. We recently identified a critical role for myeloid-derived suppressor cells (MDSCs) in S. aureus biofilm persistence. Proinflammatory signals induce MDSC recruitment and activation in tumor models; however, the mechanisms responsible for MDSC homing to sites of biofilm infection are unknown. In this study, we report that several cytokines (IL-12p40, IL-1β, TNF-α, and G-CSF) and chemokines (CXCL2, CCL5) were significantly elevated in a mouse model of S. aureus PJI. This coincided with significantly increased MDSC infiltrates concomitant with reduced monocyte, macrophage, and T cell influx compared with uninfected animals. Of the cytokines detected, IL-12 was of particular interest based on its ability to possess either pro- or anti-inflammatory effects mediated through p35-p40 heterodimers or p40 homodimers, respectively. MDSC recruitment was significantly reduced in both p40 and p35 knockout mice, which resulted in enhanced monocyte and neutrophil influx and bacterial clearance. Adoptive transfer of wild-type MDSCs into infected p40 knockout animals worsened disease outcome, as evidenced by the return of S. aureus burdens to levels typical of wild-type mice. Tissues obtained from patients undergoing revision surgery for PJI revealed similar patterns of immune cell influx, with increased MDSC-like cells and significantly fewer T cells compared with aseptic revisions. These findings reveal a critical role for IL-12 in shaping the anti-inflammatory biofilm milieu by promoting MDSC recruitment.
authors.affiliation: Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Cortney E
authors.initials: CE
authors.lastname: Heim
authors.affiliation: Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Debbie
authors.initials: D
authors.lastname: Vidlak
authors.affiliation: Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Tyler D
authors.initials: TD
authors.lastname: Scherr
authors.affiliation: Departments of Orthopaedic Surgery and Rehabilitation, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Curtis W
authors.initials: CW
authors.lastname: Hartman
authors.affiliation: Departments of Orthopaedic Surgery and Rehabilitation, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Garvin
authors.affiliation: Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Tammy
authors.initials: T
authors.lastname: Kielian
mesh_terms: D000818:Animals; D018441:Biofilms; D004195:Disease Models, Animal; D006801:Humans; D053765:Interleukin-12 Subunit p35 / Q000235:genetics / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D019637:Orthopedic Procedures / Q000009:adverse effects*; D019736:Prostheses and Implants; D016459:Prosthesis-Related Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013203:Staphylococcal Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013211:Staphylococcus aureus / Q000502:physiology*
chemical_list: C508859:Il12a protein, mouse; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40