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.

癫痫持续状态 (SE) 后会发生多维炎症反应，部分由环加氧酶 2 介导的前列腺素 EP2 受体激活驱动。炎症反应的典型特征是星形细胞增多症、小胶质细胞增多症、血脑屏障 (BBB) 侵蚀、炎性细胞因子的形成和血源性单核细胞的脑浸润。我们之前的研究表明，抑制单核细胞脑侵袭或全身给药 EP2 受体拮抗剂可减轻 SE 的多种有害后果。在这里，我们确定了 EP2 拮抗作用的效果，这些作用通过免疫骨髓细胞中 EP2 受体的条件消融而重现，并表明全身性 EP2 拮抗作用会阻止雄性小鼠的单核细胞进入大脑。在 EP2 条件性 KO 小鼠中，毛果芸香碱 SE 后海马 IL-6 的诱导几乎消失。在 EP2 充足的小鼠中，SE 后皮层中的血清白蛋白水平（BBB 分解的一种衡量指标）显着更高，但在 EP2 条件性 KO 中则不然。先天免疫细胞中的 EP2 缺乏加速了 SE 后疾病行为的恢复。令人惊讶的是，髓系条件性 KO 并未缓解神经变性。全身性 EP2 拮抗作用可防止单核细胞脑浸润，并提供比髓样 EP2 消融更广泛的 SE 诱导效应拯救，包括神经保护和更广泛的炎症介质抑制。报告基因表达表明 CD11b 驱动的 Cre 的细胞靶标是循环骨髓细胞，但出人意料的是，不是小胶质细胞。这些发现表明免疫骨髓细胞上 EP2 受体的激活导致行为的严重缺陷并在 SE 后破坏 BBB。全身性 EP2 拮抗作用的好处可部分归因于阻止血源性单核细胞的大脑募集。

重要性声明持续的癫痫发作会降低生活质量，促进癫痫的发展，并且可能是致命的。我们之前确定前列腺素 EP2 受体的激活是癫痫发作不良后果的驱动因素。然而，相关的 EP2 表达细胞类型仍不清楚。在这里，我们将外周先天免疫细胞确定为癫痫发作的 EP2 相关负面后果的驱动因素。从外周免疫细胞中去除 EP2 是有益的，可以消除关键炎症细胞因子的产生，加速体重反弹，并限制行为缺陷。这些发现证明 EP2 参与外周免疫和脑内皮细胞会导致 SE 的有害影响，并将有助于开发有益疗法，以提高长期癫痫发作患者的生活质量。