The paradigm for neutrophil mediated pathogenesis in infection is exemplified by bacterial meningitis caused by Streptococcus pneumoniae (Spn) leading to clinical trials of non-specific anti-inflammatory corticosteroids as an adjunct to antibacterial treatment ( 4). Neutrophil recruitment to the site of bacterial and fungal infections is critical for microbial clearance, but their accumulation can also cause local tissue injury by release of reactive oxygen and nitrogen species and proteolytic enzymes, and by generation of pro-inflammatory mediators that further amplify the inflammatory cascade ( 1– 3). In view of the striking redundancy in inflammatory cytokines that stimulate pericytes and in the neutrophil chemokines they produce, we propose that the mechanism of chemokine translocation may offer the most effective therapeutic target to reduce neutrophil mediated pathology in pyogenic meningitis. Our data support a model in which microbial sensing by perivascular macrophages generates an inflammatory cascade where pericytes serve to amplify production of neutrophil chemokines that are translocated across the endothelial barrier to act directly on circulating neutrophils. Pericyte mediated amplification of neutrophil transmigration was independent of transcriptional responses by endothelia, but could be mediated by direct chemokine translocation across the endothelial barrier. Instead, we show that paracrine signalling by multiple cytokines from monocyte derived macrophages drives transcriptional upregulation of multiple neutrophil chemokines by pericytes. In our model, neither pericytes nor endothelia responded directly to bacterial stimulation. In response to inflammatory cues, they significantly enhance neutrophil transmigration across the endothelial barrier, without increasing the permeability to small molecules. We show that pericytes augment endothelial barrier formation. We tested the hypothesis that human brain vascular pericytes (HBVP) contribute to neutrophil extravasation in a transwell model of the cerebral post-capillary venule.
Attention has focussed on neutrophil interactions with endothelia, but data from mouse models also point to a role for the underlying pericyte layer, as well as perivascular macrophages, the only other cell type found within the perivascular space in the cerebral microvasculature. Insufficient knowledge of the mechanisms that amplify neutrophil extravasation has limited innovation in therapeutic targeting of neutrophil mediated pathology. Excessive neutrophil extravasation can drive immunopathology, exemplified in pyogenic meningitis caused by Streptococcus pneumoniae infection.
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