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Updated: Apr 16, 2026
A Mouse Model to Assess Innate Immune Response to Staphylococcus aureus Infection
Published on: February 28, 2019
IL-12 promotes myeloid-derived suppressor cell recruitment and bacterial persistence during Staphylococcus aureus
Cortney E Heim1, Debbie Vidlak1, Tyler D Scherr1
1Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.
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.
Insights
Myeloid-derived suppressor cells (MDSCs) drive Staphylococcus aureus biofilm infections. Interleukin-12 (IL-12) promotes MDSC recruitment, hindering bacterial clearance and worsening prosthetic joint infections (PJIs).
Area of Science:
- Immunology
- Microbiology
- Biomedical Engineering
Background:
- Staphylococcus aureus is a primary cause of prosthetic joint infections (PJIs), characterized by persistent biofilm formation.
- Myeloid-derived suppressor cells (MDSCs) have been identified as crucial for S. aureus biofilm persistence.
- Mechanisms of MDSC homing to biofilm infection sites remain largely unknown.
Purpose of the Study:
- To investigate the mechanisms of myeloid-derived suppressor cell (MDSC) recruitment in Staphylococcus aureus prosthetic joint infections (PJIs).
- To elucidate the role of specific cytokines and chemokines in mediating MDSC infiltration during S. aureus PJI.
- To determine the impact of IL-12 signaling on immune cell dynamics and bacterial clearance in PJI.
Main Methods:
- Utilized a mouse model of S. aureus PJI to analyze cytokine and chemokine profiles.
- Quantified immune cell infiltrates, including MDSCs, monocytes, macrophages, and T cells, in infected tissues.
- Employed knockout mouse models (p40 and p35) and adoptive cell transfer to assess the function of IL-12 and MDSCs.
- Examined immune cell infiltration patterns in human PJI patient tissues.
Main Results:
- Elevated levels of cytokines (IL-12p40, IL-1β, TNF-α, G-CSF) and chemokines (CXCL2, CCL5) were observed in the S. aureus PJI mouse model.
- Increased MDSC infiltration correlated with reduced influx of monocytes, macrophages, and T cells.
- MDSC recruitment was significantly diminished in p40 and p35 knockout mice, leading to enhanced neutrophil influx and bacterial clearance.
- Adoptive transfer of wild-type MDSCs into p40 knockout mice restored bacterial burdens to wild-type levels.
- Human PJI tissues showed increased MDSC-like cells and decreased T cells compared to aseptic revisions.
Conclusions:
- Interleukin-12 (IL-12) plays a critical role in promoting MDSC recruitment during S. aureus PJI.
- IL-12 contributes to an anti-inflammatory environment that favors biofilm persistence.
- Targeting the IL-12/MDSC axis may offer a therapeutic strategy for managing S. aureus prosthetic joint infections.
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