Opposing effects of prostaglandin receptor EP2 signaling in mouse immune cells and neurons after status epilepticus

Abstract

A multidimensional inflammatory response ensues after status epilepticus (SE), driven partly by cyclooxygenase-2 mediated activation of prostaglandin EP2 receptors. Here we identify those effects of EP2 antagonism that are reproduced by conditional ablation of EP2 receptors in immune myeloid cells and forebrain neurons. Removal of myeloid cell EP2 dampened induction of hippocampal IL-6, prevented erosion of the blood-brain barrier, accelerated weight regain, and relieved ptosis following SE. Elimination of EP2 receptor from neurons enhanced neuronal injury, elevated hippocampal induction of the pro-inflammatory cytokines, TNF and Ccl2, promoted deterioration of the blood-brain barrier, delayed weight recovery, and worsened animal posture and activity. Taken together these data highlight the complexities in neuroinflammatory signaling, wherein activation of EP2 receptors in innate immune cells is deleterious but neuronal EP2 signaling is protective. Effective treatments targeting brain prostaglandin signaling pathways should be cell targeted to be optimally effective.\n\nSignificance StatementSeizures reduce quality of life, promote the development of epilepsy, and can be fatal. We previously identified inflammation, via prostaglandin receptor EP2 activation, as a driver of undesirable seizure-induced effects. However, the relevant EP2-expressing cell types remain unclear. We identify innate immune cells as a driver of the EP2-related negative consequences of seizures, whereas neuronal EP2 signaling is protective. Genetic removal of EP2 from immune cells was beneficial, accelerating weight gain and limiting behavioral deficits. Elimination of EP2 from neurons was harmful, worsening behavioral deficits and promoting neuronal damage. These findings enhance our understanding of the complex inflammatory processes engaged after seizures and will assist in the development of beneficial therapies to enhance quality of life in individuals susceptible to seizures.