Nociceptors and Macrophages in Bacterial Meningitis: Partners in Crime?
Nociceptors and Macrophages in Bacterial Meningitis: Partners in Crime?
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细菌性脑膜炎中的伤害感受器和巨噬细胞：犯罪伙伴？
DOI：
10.1007/s12264-023-01141-7
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发表时间：
2024
影响因子：
5.6
通讯作者：
Hu,Hongzhen
中科院分区：
文献类型：
--
作者：
Gao,Fang;Hu,Hongzhen
细菌性脑膜炎是一种严重的，可能危及生命的感染，影响大脑和脊髓周围的保护层，称为脑膜。几种类型的细菌，包括肺炎链球菌，脑膜炎奈瑟菌和流感嗜血杆菌，可以引起这种情况。某些人群，如婴儿、儿童、免疫功能低下的成人和老年人，特别容易受到这些病原体的影响。细菌性脑膜炎的症状可以突然出现，可能包括高烧，严重和持续的头痛，颈部僵硬，呕吐，对光敏感，精神状态混乱或变化[1，2]。在婴儿中识别这些症状可能更具挑战性，并可能导致长期残疾或死亡[3]。尽管疫苗有效，但了解细菌如何侵入大脑以及我们的先天免疫系统如何对感染做出反应至关重要（图1）。Pinho-Ribeiro等人最近的一项研究表明，细菌感染对Nav 1有直接影响。8+伤害感受器，导致神经肽降钙素基因相关肽（CGRP）的释放，从而抑制脑膜中的宿主防御并加重细菌性脑膜炎[4]。作者首先通过注射S.肺炎链球菌或无乳链球菌（S.无乳）静脉注射，其复制细菌病原体通过人类血液的传播。随后，作者研究了细菌入侵的时间轴。值得注意的是，细菌首先到达硬脑膜，其次是软脑膜和蛛网膜，最后是大脑。作者证明，消除Nav 1. Nav 1中有8+伤害感受器。8-Cre：：DTA小鼠通过基因消融或使用树脂毒素（RTX），一种非常有效的TRPV 1激动剂，化学消融TRPV 1+伤害感受器，导致中枢神经系统（CNS）中的细菌负荷减少。然而，当细菌绕过硬脑膜直接注入脑池时，与对照组相比，伤害感受器的消除不再对感染产生影响。这表明伤害感受器调节细菌入侵，并且这发生在细菌进入大脑之前。头痛是细菌性脑膜炎的常见表现，其原因是三叉神经节（TG）伤害感受器对脑膜的神经支配。作者提出了一个假设，即细菌性脑膜炎中TG伤害感受器的激活可能导致CGRP从硬脑膜中的神经末梢释放，从而引起头痛[5]。这项研究的结果支持了这一假设，因为在注射S.肺炎。此外，TG神经元直接与S.肺炎。这些结果表明细菌对TG伤害感受器的直接作用。这一观察结果与先前的一项研究一致，该研究报告了急性细菌性脑膜炎和脓毒症患者的CGRP动脉水平升高[6]。
Bacterial meningitis is a serious and potentially life-threatening infection that affects the protective layers surrounding the brain and spinal cord, known as the meninges. Several types of bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae, can cause this condition. Certain populations, such as infants, children, immunocompromised adults, and the elderly, are particularly vulnerable to these pathogens. Symptoms of bacterial meningitis can manifest suddenly and may include high fever, severe and persistent headache, stiff neck, vomiting, sensitivity to light, and confusion or changes in mental state [1, 2]. Identifying these symptoms in infants can be more challenging and may lead to long-term disability or death [3]. Despite the effectiveness of vaccines, it is crucial to understand how bacteria invade the brain and how our innate immune system responds to infection (Fig. 1). A recent study by Pinho-Ribeiro et al. demonstrated that bacterial infections have a direct impact on Nav1. 8+ nociceptors in the meninges, resulting in the release of neuropeptide calcitonin gene-related peptide (CGRP), which dampens host defenses in the meninges and exacerbates bacterial meningitis [4]. The authors first induced bacterial meningitis in mice by injecting S. pneumoniae or Streptococcus agalactiae (S. agalactiae) intravenously, which replicates the spread of bacterial pathogens through the bloodstream in humans. Subsequently, the authors investigated the timeline of bacterial invasion. Notably, the bacteria first reached the dura mater, followed by the pia and arachnoid, and finally the brain. The authors demonstrated that the elimination of Nav1. 8+ nociceptors in Nav1. 8-Cre:: DTA mice through genetic ablation or the use of resiniferatoxin (RTX), an extremely potent TRPV1 agonist, to chemically ablate TRPV1+ nociceptors resulted in reduced bacterial loads in the central nervous system (CNS). However, when bacteria were injected directly into the cistern bypassing the dura, the elimination of nociceptors no longer had an impact on the infection compared to the control group. This suggests that nociceptors regulate bacterial invasion, and this occurs prior to the bacteria entering the brain. Headaches are a common manifestation of bacterial meningitis due to the innervation of the meninges by paininducing trigeminal ganglia (TG) nociceptors. The authors proposed a hypothesis that the activation of TG nociceptors in bacterial meningitis could lead to the release of CGRP from nerve terminals in the dura, thereby causing headaches [5]. The findings of the study support this hypothesis, as an increase in CGRP release was observed in meninges explants following injection of S. pneumoniae. Additionally, TG neurons released CGRP when they were incubated directly with S. pneumoniae. These results suggest a direct action of bacteria on TG nociceptors. This observation aligns with a previous study that reported elevated arterial levels of CGRP in patients with acute bacterial meningitis and sepsis [6].