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.SIGNIFICANCE STATEMENT Unabated
seizures reduce quality of life, promote the development of
epilepsy, and can be fatal. We previously identified activation of
prostaglandin EP2 receptors as a driver of undesirable consequences of
seizures. However, the relevant EP2-expressing cell types remain unclear. Here we identify peripheral innate immune cells as a driver of the EP2-related negative consequences of
seizures. Removal of EP2 from peripheral immune cells was beneficial, abolishing production of a key inflammatory
cytokine, accelerating weight regain, and limiting behavioral deficits. These findings provide evidence that EP2 engagement on peripheral immune and brain endothelia contributes to the deleterious effects of SE, and will assist in the development of beneficial
therapies to enhance quality of life in individuals who suffer prolonged
seizures.