Title: P2x7 Receptor Activation and Estrogen Status Drive Neuroinflammatory Mechanisms in a Rat Model for Dry Eye.
Title: P2x7 Receptor Activation and Estrogen Status Drive Neuroinflammatory Mechanisms in a Rat Model for Dry Eye.
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DOI：
10.3389/fphar.2022.827244
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发表时间：
2022
影响因子：
5.6
通讯作者：
Olson, Julie K.
中科院分区：
文献类型：
--
作者：
Bereiter, David A.;Rahman, Mostafeezur;Ahmed, Fabeeha;Thompson, Randall;Nhungoc Luong;Olson, Julie K.
干眼病(DED)被认为是一种慢性炎症性疾病，泪液渗透压增加，泪膜完整性丧失。DED通常伴有不良的眼部症状，女性比男性更常见。DED的眼部痛觉过敏的基础仍不确定，然而，外周和中枢神经机制都有牵连。采用眼眶外腺切除缺水DED模型，观察周围和中央三叉神经通路中非神经细胞表达的嘌呤能受体亚型7，P2X7R的激活是否与持续性眼痛觉过敏有关。三叉神经脑干切片的密度计量学显示，与雌二醇处理的假雌鼠相比，接受雌二醇治疗的DED雌鼠的P2X7R、髓系细胞标记物Iba1和炎症体NLRP3的表达增加，而DED雄鼠和未给予雌二醇的DED雌鼠的表达略有变化。DED大鼠未见免疫细胞渗入三叉神经脑干的证据；然而，小胶质细胞激活的标记物(IBA1)在所有组均增加。分离的小胶质细胞表达高水平的P2X7R、P2X4R、IL-1β(Ι、IL-1、β、nLRP3和iNOS。此外，与未治疗的DED雌性相比，接受雌激素治疗的DED雌性鼠的P2X7R、IL-1β和NLRP3的表达有更大的增加。用高渗盐水(HS)滴眼诱发的眼轮匝肌活动(OOemg)作为眼部痛觉过敏的替代指标，各DED组大鼠的眼轮匝肌活动(OOemg)均明显高于假手术组。与假手术组相比，全身性二甲胺四环素降低了所有DED组的HS诱发的OOEMG。三叉神经尾侧脑干局部微量注射P2X7R拮抗剂(A804598)可显著降低所有DE组的HS诱发的OOemg活动，而假手术组的反应不受影响。三叉神经节内注射针对P2X7R的siRNA可显著降低各DED组HS诱发的OOemg活性，而对假手术组的诱发反应无明显影响。这些结果表明，三叉神经痛通路中心和外周部位的P2X7R的激活导致DED男性和女性眼部痛觉过敏和小胶质细胞激活的增加。在缺水的DED模型中，女性雌激素治疗进一步放大了眼部痛觉过敏和神经免疫反应。
Dry eye disease (DED) is recognized as a chronic inflammatory condition with an increase in tear osmolarity and loss of tear film integrity. DED is often accompanied by adverse ocular symptoms which are more prevalent in females than males. The basis for ocular hyperalgesia in DED remains uncertain; however, both peripheral and central neural mechanisms are implicated. A model for aqueous deficient DED, exorbital gland excision, was used to determine if activation of the purinergic receptor subtype 7, P2X7R, expressed by non-neural cells in peripheral and central trigeminal nerve pathways, contributed to persistent ocular hyperalgesia. Densitometry of trigeminal brainstem sections revealed increases in P2X7R, the myeloid cell marker Iba1, and the inflammasome, NLRP3, of estradiol-treated DED females compared to estradiol-treated sham females, while expression in DED males and DED females not given estradiol displayed minor changes. No evidence of immune cell infiltration into the trigeminal brainstem was seen in DED rats; however, markers for microglia activation (Iba1) were increased in all groups. Isolated microglia expressed increased levels of P2X7R and P2X4R, IL-1β (Ιnterleukin-1β), NLRP3, and iNOS (nitric oxide synthase). Further, estradiol-treated DED females displayed greater increases in P2X7R, IL-1β and NLRP3 expression compared to untreated DED females. Orbicularis oculi muscle activity (OOemg) evoked by ocular instillation of hypertonic saline (HS) was recorded as a surrogate measure of ocular hyperalgesia and was markedly enhanced in all DED groups compared to sham rats. Systemic minocycline reduced HS-evoked OOemg in all DED groups compared to sham rats. Local microinjection in the caudal trigeminal brainstem of an antagonist for P2X7R (A804598) greatly reduced HS-evoked OOemg activity in all DE groups, while responses in sham groups were not affected. Intra-trigeminal ganglion injection of siRNA for P2X7R significantly reduced HS-evoked OOemg activity in all DED groups, while evoked responses in sham animals were not affected. These results indicated that activation of P2X7R at central and peripheral sites in trigeminal pain pathways contributed to an increase in ocular hyperalgesia and microglia activation in DED males and females. Estrogen treatment in females further amplified ocular hyperalgesia and neuroimmune responses in this model for aqueous deficient DED.
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DOI：
10.1097/icl.0b013e3181c739ad
发表时间：
2010-01-01
影响因子：
2.3
作者：
Asbell, Penny A.;Spiegel, Scott
通讯作者：
Spiegel, Scott
小胶质细胞 P2X7 受体和下游信号通路参与脊髓伤害性反应的长期增强
影响因子：
15.1
作者：
Chu, Yu-Xia;Zhang, Yan;Zhao, Zhi-Qi
通讯作者：
Zhao, Zhi-Qi
影响因子：
8.8
作者：
Guneykaya, Dilansu;Ivanov, Andranik;Wolf, Susanne A.
通讯作者：
Wolf, Susanne A.
影响因子：
3.5
作者：
Guzman-Aranguez, Ana;Perez de Lara, Maria J.;Pintor, Jesus
通讯作者：
Pintor, Jesus
影响因子：
11.2
作者：
Baron, Ralf;Hans, Guy;Dickenson, Anthony H.
通讯作者：
Dickenson, Anthony H.