Abstract Details

Title A Time-dependent Transcriptomic Program for Neutrophil Recruitment in the Choroid Plexus After Traumatic Brain Injury

Topic Neuro Trauma and Critical Care

Presentation(s) S26 - Neuro Trauma and Sports Neurology (1:36 PM-1:48 PM)

Poster/Presentation
Number 004

Background Neuroinflammation is a critical component of secondary injury after TBI. Evidence suggests that the choroid plexus is a key site for immune recruitment to the brain, but little is known about its response to TBI.

Objective To describe the choroid plexus response to traumatic brain injury (TBI).

Design/Methods Mice underwent controlled cortical impact (CCI) or sham surgery. Each lateral ventricle choroid plexus was isolated at 3, 6, or 24-hours post CCI in biological triplicate, for next generation sequencing and analyzed using DESeq2. Samples from an independent animal cohort were isolated 24 hours after injury for immunohistochemistry.

Results The choroid plexus transcriptome revealed a biphasic, pro-inflammatory response to injury, with Gene Ontology categorizations “inflammatory response”, “immune response”, and “cellular response to lipopolysaccharide” as the most significant terms. Six hours after CCI, neutrophil chemoattractants Cxcl1 and Cxcl2 (fold change 1.3⋅103 and 7.9⋅104, respectively) and transcription factors Fos, Jun, and Egr1 were the most upregulated genes in the ipsilateral choroid plexus. Twenty-four hours post-CCI, Mmp3, Mmp12, and Lcn2, genes encoding matrix metalloproteases and metalloprotease-associated proteins, were among the most upregulated genes. Immunohistochemistry validated these findings with a large increase in neutrophils in the ipsilateral choroid plexus 24 hours after CCI. Upregulated genes at 24 hours post-CCI were notably enriched in targets of JUNB and FOSL2, which were themselves upregulated by3 hours after injury suggesting potential feed-forward regulation.

Conclusions The choroid plexus exhibits a biphasic, time-dependent transcriptomic response in the first 24 hours after TBI. Bioinformatic analysis suggests chemoattractants and key transcription factors are expressed in the first 6 hours after injury which recruit neutrophils to the choroid plexus. At 24 hours after injury, expression switches to metalloproteases that may be involved in permeabilizing the blood-CSF-barrier. These results may inform a strategy to target neutrophil entry into the brain through the choroid plexus to limit neuroinflammation after TBI.

Authors/Disclosures
Prajwal Ciryam, MD, PhD (University of Maryland School of Medicine) PRESENTER	The institution of Dr. Ciryam has received research support from Henry M. Jackson Foundation. The institution of Dr. Ciryam has received research support from Passano Foundation. The institution of Dr. Ciryam has received research support from GEn1E Lifesciences. The institution of Dr. Ciryam has received research support from Brain Aneurysm Foundation. The institution of Dr. Ciryam has received research support from Neurocritical Care Foundation. The institution of Dr. Ciryam has received research support from Center for Shock, Trauma, and Anesthesiology Research, University of Maryland.
Brad Wilhelmy	Mr. Wilhelmy has nothing to disclose.
Orest Tsymbalyuk (University of Maryland School of Medicine)	No disclosure on file
Timothy Zhang	Timothy Zhang has nothing to disclose.
Alexandra Vesselinov	Ms. Vesselinov has nothing to disclose.
Kaspar Keledjian, MD	Dr. Keledjian has nothing to disclose.
Vladimir Gerzanich, MD, PhD	The institution of Dr. Gerzanich has received research support from NIH.
J. Marc Simard, MD, PhD (University of Maryland Neurosurgery)	Dr. Simard has nothing to disclose.

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