Peng Lin, Li Hongbing, Zhang Cheng, Jiang Weiwei
Department of Gynecologic Oncology of Hubei Cancer Hospital, Hubei Province, 430079, Wuhan, China.
Emergency Department of the First People's Hospital, Guiyang, Guizhou Province, 550002, China.
Transl Neurosci. 2024 Aug 14;15(1):20220345. doi: 10.1515/tnsci-2022-0345. eCollection 2024 Jan 1.
Our previous studies have shown that activating α7nAChRs suppresses systemic inflammation and immunity through the cholinergic anti-inflammatory pathway (CAP) in early sepsis. Now that the medullary visceral zone (MVZ) is the center of CAP and responsible for regulating systemic inflammation, what changes will occur in MVZ's pathology and function in sepsis, especially when interfering with α7nAChRs? Does activation of MVZ's α7nAChRs contribute to the inhibition of systemic inflammation? To clarify these issues, we explored the systemic inflammation and immunity state by detecting serum levels of TNF-α, IL-6, HMGB1, sCD14, and CD4CD25Treg and TH17 lymphocytes percentage, meanwhile, we analyzed the apoptosis of cholinergic and catecholaminergic neurons and the expressions of tyrosine hydroxylase (TH) and choline acetyltransferase (CHAT) in MVZ in sepsis and the interfering effects on α7nAChRs. In this study, we found that in sepsis, serum TNF-α, IL-6, HMGB1, sCD14, CD4CD25Treg, and TH17 lymphocytes significantly increased and the ratio of Treg/TH17 significantly decreased, cholinergic and catecholaminergic neurons underwent apoptosis with low expressions of TH and CHAT in MVZ; activation of α7nAChRs not only significantly decreased the levels of septic serum TNF-α, IL-6, HMGB1, sCD14, and TH17 lymphocytes ( ＜ 0.05), but also significantly reduced cholinergic and catecholaminergic neurons' apoptosis, and promoted expressions of TH/CHAT. Our study reveals that sepsis undermines MVZ through neuroinflammation which contributes to the uncontrolled systemic inflammation. Activating central α7nAChRs is not only helpful to restore MVZ's structure and function but also beneficial to subside the inflammatory storm in sepsis. Even if MVZ is damaged in sepsis, cholinergic neurons in MVZ still regulate the systemic inflammation stably.
我们之前的研究表明，在早期脓毒症中，激活α7烟碱型乙酰胆碱受体（α7nAChRs）可通过胆碱能抗炎通路（CAP）抑制全身炎症和免疫。鉴于延髓内脏带（MVZ）是CAP的中心且负责调节全身炎症，那么在脓毒症中，尤其是干扰α7nAChRs时，MVZ的病理和功能会发生哪些变化？激活MVZ的α7nAChRs是否有助于抑制全身炎症？为了阐明这些问题，我们通过检测血清中肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、高迁移率族蛋白B1（HMGB1）、可溶性CD14（sCD14）水平以及CD4CD25调节性T细胞（Treg）和辅助性T细胞17（TH17）淋巴细胞百分比来探究全身炎症和免疫状态，同时，我们分析了脓毒症中MVZ内胆碱能和儿茶酚胺能神经元的凋亡情况以及酪氨酸羟化酶（TH）和胆碱乙酰转移酶（CHAT）的表达，还有对α7nAChRs的干扰作用。在本研究中，我们发现，在脓毒症中，血清TNF-α、IL-6、HMGB1、sCD14、CD4CD25Treg和TH17淋巴细胞显著增加，Treg/TH17比值显著降低，胆碱能和儿茶酚胺能神经元发生凋亡，MVZ中TH和CHAT表达较低；激活α7nAChRs不仅显著降低脓毒症血清TNF-α、IL-6、HMGB1、sCD14和TH17淋巴细胞水平（P＜0.05），还显著减少胆碱能和儿茶酚胺能神经元的凋亡，并促进TH/CHAT的表达。我们的研究表明，脓毒症通过神经炎症破坏MVZ，这导致全身炎症失控。激活中枢α7nAChRs不仅有助于恢复MVZ的结构和功能，还有利于消退脓毒症中的炎症风暴。即使脓毒症中MVZ受损，MVZ中的胆碱能神经元仍能稳定调节全身炎症。
