AUTHOR=Soliman Eman , Mills Jatia , Ju Jing , Kaloss Alexandra M. , Basso Erwin Kristobal Gudenschwager , Groot Nathalie , Kelly Colin , Kowalski Elizabeth A. , Elhassanny Mohamed , Chen Michael , Wang Xia , Theus Michelle H. 

TITLE=Conditional Deletion of EphA4 on Cx3cr1-Expressing Microglia Fails to Influence Histopathological Outcome and Blood Brain Barrier Disruption Following Brain Injury

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=14

YEAR=2021

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2021.747770

DOI=10.3389/fnmol.2021.747770

ISSN=1662-5099

ABSTRACT=<p>Erythropoietin-producing human hepatocellular receptors play a major role in central nervous system injury. Preclinical and clinical studies revealed the upregulation of erythropoietin-producing human hepatocellular A4 (EphA4) receptors in the brain after acute traumatic brain injury. We have previously reported that Cx3cr1-expressing cells in the peri-lesion show high levels of EphA4 after the induction of controlled cortical impact (CCI) injury in mice. Cx3cr1 is a fractalkine receptor expressed on both resident microglia and peripheral-derived macrophages. The current study aimed to determine the role of microglial-specific EphA4 in CCI-induced damage. We used <italic>Cx3cr1</italic><sup><italic>CreER</italic>/+</sup> knock-in/knock-out mice, which express EYFP in Cx3cr1-positive cells to establish microglia, EphA4-deficient mice following 1-month tamoxifen injection. Consistent with our previous findings, induction of CCI in wild-type (WT) <italic>Cx3cr1</italic><sup><italic>CreER</italic>/+</sup><italic>EphA4</italic><sup>+/+</sup> mice increased EphA4 expression on EYFP-positive cells in the peri-lesion. To distinguish between peripheral-derived macrophages and resident microglia, we exploited GFP bone marrow-chimeric mice and found that CCI injury increased EphA4 expression in microglia (TMEM119+GFP–) using immunohistochemistry. Using <italic>Cx3cr1</italic><sup><italic>CreER</italic>/+</sup><italic>EphA4</italic><sup><italic>f</italic>/<italic>f</italic></sup> (KO) mice, we observed that the EphA4 mRNA transcript was undetected in microglia but remained present in whole blood when compared to WT. Finally, we found no difference in lesion volume or blood-brain barrier (BBB) disruption between WT and KO mice at 3 dpi. Our data demonstrate a nonessential role of microglial EphA4 in the acute histopathological outcome in response to CCI.</p>