No abstract

Brain pericyte is unique and indispensable part of blood-brain barrier (BBB), and contributes to several pathological processes in traumatic brain injury (TBI). However, the cellular and molecular mechanisms about how pericyte is regulated in damaged brain are largely unknown. Here, we show that neutrophil extracellular traps (NETs) formation induces the appearance of CD11b+ pericytes post TBI. These CD11b+ pericytes subsets are characterized with increased permeability and pro-inflammatory profiles compared to CD11b- pericytes. Moreover, histones from NETs by Dectin-1 facilitate CD11b induction on brain pericytes in PKC-c-Jun dependent manner, conferring neuroinflammation and BBB dysfunction post TBI. These data indicate that "neutrophil-NETs-pericyte" and "histones-Dectin-1-CD11b" are possible mechanisms for pericyte’s activation and dysfunction. Targeting at NETs formation and Dectin-1 are promising ways for TBI treatments.

BackgroundBlood-brain barrier (BBB) disruption and leukocyte infiltration are two pathological features post traumatic brain injury (TBI). However, the role of circulating leukocytes in BBB disruption and the crosstalk between them are not fully elucidated. Neutrophil is the most abundant circulating cell type that migrates into brain tissue when TBI occurs instantly, while brain pericyte occupies a strategic position between circulating cell and interstitial space in BBB. Understanding their interactions is essential to provide insight into the intrinsic relationship and identify biological targets for TBI treatments. MethodsBy analyzing brain tissues from TBI patients and mouse TBI model through immunohistochemical method and flow cytometry, we build the relationship between neutrophils, neutrophil extracellular traps (NETs) and brain pericyte. The components of NETs-related medium were investigated by proteomics and metabolomics to decipher the factors directly regulating pericytes. The molecular mechanisms were deeply explored by WB/CHIP/RT-PCR in primary brain pericyte/pericyte cell line MBVP treated with NETs-formed medium or specific NETs components. In mice TBI model, we also explored the possible therapeutic approaches for TBI treatment that targeting at the axis of neutrophil-NETs-pericyte. ResultsNETs formation is highly enhanced post TBI, inducing the appearance of CD11b expressing brain pericyte simultaneously. This novel CD11b+ pericyte subset is characterized with increased permeability and pro-inflammatory profiles. Mechanistically, recognition of histones from NETs by Dectin-1 on pericyte contributes to CD11b induction in protein kinase C (PKC)-c-Jun-dependent manner. Transcription factor c-Jun directly binds to the promoter sequence of CD11b to enhance its expression in pericyte, conferring pericyte activation, BBB disruption and aggravated neutrophil infiltration post TBI. Either inhibiting NETs formation by Cl-Amidine or blocking Dectin-1 by Laminarin are both beneficial for decreasing neutrophil infiltration and brain pericyte activation post TBI. ConclusionsThese results unfold that “neutrophil-NETs-pericyte” and “histones-Dectin-1-CD11b” are possible cellular and molecular mechanisms for building connection between BBB damage and neutrophil infiltration. Targeting at NETs formation and Dectin-1 are promising treatments for improving neurological outcomes of TBI patients.