CXC chemokine receptor-2 ligands are required for neutrophil-mediated host defense in experimental brain abscesses
T Kielian1, B Barry, W F Hickey
1Department of Pathology, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA. tammy.kielian@dartmouth.edu
Abstract:
We have developed a mouse brain abscess model by using Staphylococcus aureus, one of the main etiologic agents of brain abscesses in humans. Direct damage to the blood-brain barrier was observed from 24 h to 7 days after S. aureus exposure as demonstrated by the accumulation of serum IgG in the brain parenchyma. Evaluation of brain abscesses by immunohistochemistry and flow cytometry revealed a prominent neutrophil infiltrate. To address the importance of neutrophils in the early containment of S. aureus infection in the brain, mice were transiently depleted of neutrophils before implantation of bacteria-laden beads. Neutrophil-depleted animals consistently demonstrated more severe brain abscesses and higher CNS bacterial burdens compared with control animals. S. aureus led to the induction of numerous chemokines in the brain, including macrophage-inflammatory protein (MIP)-1alpha/CCL3, MIP-1beta/CCL4, MIP-2/CXCL1, monocyte chemoattractant protein-1/CCL2, and TCA-3/CCL1, within 6 h after bacterial exposure. These chemokines also were expressed by both primary cultures of neonatal mouse microglia and astrocytes exposed to heat-inactivated S. aureus in vitro. Because neutrophils constitute the majority of the cellular infiltrate in early brain abscess development, subsequent analysis focused on MIP-2 and KC/CXCL1, two neutrophil-attracting CXC chemokines. Both MIP-2 and KC protein levels were significantly elevated in the brain after S. aureus exposure. Neutrophil extravasation into the brain parenchyma was impaired in CXCR2 knockout mice and was associated with increased bacterial burdens. These studies demonstrate the importance of the CXCR2 ligands MIP-2 and KC and neutrophils in the acute host response to S. aureus in the brain.
Insights
Neutrophils are crucial for controlling Staphylococcus aureus brain infections. Their absence leads to more severe abscesses and higher bacterial loads, highlighting the importance of neutrophils and CXCR2 ligands in the acute brain response.
Area of Science:
- Neuroscience
- Immunology
- Infectious Diseases
Background:
- Staphylococcus aureus is a primary cause of human brain abscesses.
- The early host response to S. aureus in the central nervous system (CNS) is not fully understood.
Purpose of the Study:
- To investigate the role of neutrophils in the acute host response to S. aureus brain infection.
- To elucidate the mechanisms of neutrophil recruitment and their impact on bacterial containment.
Main Methods:
- Development of a mouse model of S. aureus brain abscess.
- Immunohistochemistry and flow cytometry to analyze cellular infiltration.
- Neutrophil depletion studies and analysis of chemokine expression (MIP-2, KC).
- Evaluation of bacterial burden and abscess severity in wild-type and CXCR2 knockout mice.
Main Results:
- S. aureus caused blood-brain barrier damage and significant neutrophil infiltration.
- Neutrophil depletion resulted in more severe abscesses and increased bacterial loads.
- S. aureus induced chemokines (MIP-2, KC) that attract neutrophils.
- Impaired neutrophil extravasation in CXCR2 knockout mice led to higher bacterial burdens.
Conclusions:
- Neutrophils play a critical role in controlling S. aureus brain infections.
- The CXCR2 ligands MIP-2 and KC are important for neutrophil recruitment to the brain.
- Targeting neutrophils and their signaling pathways may offer therapeutic strategies for brain abscesses.
Related Concept Videos
01:21Chemotaxis and Direction of Cell Migration
01:26Brain Abscess l: Introduction
01:26Bacterial Meningitis II: Pathophysiology
01:26Acute Inflammation II: Cellular Phase