About this item:

132 Views | 39 Downloads

Author Notes:

Nicholas H. Varvel, nvarvel@emory.edu

N.H.V., T.G., and R.D. designed research; N.H.V. and L.B.-R. performed research; N.H.V., C.E.-G., S.H.-C., D.C., A.B., A.H., L.B.-R., and R.D. analyzed data; N.H.V. wrote the first draft of the paper; N.H.V., T.G., and R.D. edited the paper; N.H.V. wrote the paper.

We thank K. Andreasson (Stanford University) for sharing EP2 flox mice and CD11b-Cre mice; Tomohiro Aoki (National Cerebral and Cardiovascular Center, Suita, Osaka, Japan) and Richard Breyer (Vanderbilt University) for EP2 global KO tissues; M. Tansey (Emory University) for use of stereology equipment; and A. Rea (Emory University) for assistance with flow sorting.

The authors declare no competing financial interests.

Subjects:

Research Funding:

This work was supported in part by Emory University Pediatric/Winship Flow Cytometry Core, Emory University Genomics Core, and National Institutes of Health, Office of the Director, National Institute of Neurological Disorders and Stroke Grants R01 NS097776 and R01 NS112308 to R.D., R01 NS112350 to N.H.V., R21 NS101167 to T.G., and National institute of Aging Grant U01 AG052460 to T.G.

This work was supported in part by the Emory University Integrated Cellular Imaging Microscopy Core of the Emory Neuroscience, National Institute of Neurological Disorders and Stroke Core Facilities Grant 5P30NS055077.

The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • Cox-2
  • EP2
  • epilepsy
  • inflammation
  • monocytes
  • status epilepticus
  • BLOOD-BRAIN-BARRIER
  • DELAYED MORTALITY
  • MICE LACKING
  • RECEPTOR
  • INFLAMMATION
  • DISEASE
  • CYCLOOXYGENASE-2
  • PROGRESSION
  • INHIBITION
  • MODEL

Peripheral Myeloid Cell EP2 Activation Contributes to the Deleterious Consequences of Status Epilepticus

Tools:

Journal Title:

JOURNAL OF NEUROSCIENCE

Volume:

Volume 41, Number 5

Publisher:

, Pages 1105-1117

Type of Work:

Article | Final Publisher PDF

Abstract:

A multidimensional inflammatory response ensues after status epilepticus (SE), driven partly by cyclooxygenase-2-mediated activation of prostaglandin EP2 receptors. The inflammatory response is typified by astrocytosis, microgliosis, erosion of the blood-brain barrier (BBB), formation of inflammatory cytokines, and brain infiltration of blood-borne monocytes. Our previous studies have shown that inhibition of monocyte brain invasion or systemic administration of an EP2 receptor antagonist relieves multiple deleterious consequences of SE. Here we identify those effects of EP2 antagonism that are reproduced by conditional ablation of EP2 receptors in immune myeloid cells and show that systemic EP2 antagonism blocks monocyte brain entry in male mice. The induction of hippocampal IL-6 after pilocarpine SE was nearly abolished in EP2 conditional KO mice. Serum albumin levels in the cortex, a measure of BBB breakdown, were significantly higher after SE in EP2-sufficient mice but not in EP2 conditional KOs. EP2 deficiency in innate immune cells accelerated the recovery from sickness behaviors following SE. Surprisingly, neurodegeneration was not alleviated in myeloid conditional KOs. Systemic EP2 antagonism prevented monocyte brain infiltration and provided broader rescue of SE-induced effects than myeloid EP2 ablation, including neuroprotection and broader suppression of inflammatory mediators. Reporter expression indicated that the cellular target of CD11b-driven Cre was circulating myeloid cells but, unexpectedly, not microglia. These findings indicate that activation of EP2 receptors on immune myeloid cells drives substantial deficits in behavior and disrupts the BBB after SE. The benefits of systemic EP2 antagonism can be attributed, in part, to blocking brain recruitment of blood-borne monocytes.

Copyright information:

© 2021 the authors

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/rdf).
Export to EndNote