单纯疱疹病毒1型感染肠神经元并通过巨噬细胞招募引发肠道功能障碍
Herpes Simplex Virus Type 1 Infects Enteric Neurons and Triggers Gut Dysfunction via Macrophage Recruitment.
摘要：
单纯疱疹病毒1型（HSV-1）是一种广泛存在于人群中的神经性病原体，感染人和啮齿动物的肠神经系统（ENS）并导致大鼠肠神经肌肉功能障碍。
尽管肌间神经丛中的炎性细胞浸润和肠神经的神经变性是患有功能性肠病的患者的共同特征，但是与HSV-1的致病关系的证据仍然未解决，主要是因为潜在的机制在很大程度上是未知的。
在该研究中，我们证明了在胃内接种HSV-1感染肌间神经丛内的神经元，导致肠道的功能和结构改变。通过用HSV-1复制缺陷型菌株感染小鼠，我们发现胃肠神经肌肉异常不依赖于病毒复制。实际上，暴露于UV灭活的HSV-1的肠神经元产生单核细胞趋化蛋白-1（MCP-1 / CCL2）以在纵向肌肌间神经丛中募集活化的巨噬细胞。
浸润性巨噬细胞产生活性氧和氮活性物并直接损害肠神经元，导致胃肠动力障碍。在HSV-1感染的小鼠中，通过体内施用（i）含有二氯亚甲基双膦酸（氯膦酸盐）以消耗组织巨噬细胞的脂质体来改善肠神经肌肉功能障碍，（ii）CCR2趋化因子受体拮抗剂RS504393阻断CCL2 / CCR2途径，（iii） ）Nω-硝基-L-精氨酸甲酯盐酸盐（L-NAME）和AR-C 102222，用于淬灭通过iNOS产生的氮活性物质的产生。
总体而言，这些数据表明HSV-1感染通过产生特定的化学引诱因子使肠神经元募集巨噬细胞。由此产生的炎症反应对于肠动力障碍是强制性的。这些发现提供了在HSV-1感染后肠道中发生的神经免疫通讯的见解，并且允许识别胃肠疾病的原始病理生理机制以及新治疗靶标的鉴定。
关键词：
肠神经病;炎症;巨噬细胞募集;神经肌肉功能障碍;神经病毒
Herpes Simplex Virus Type 1 Infects Enteric Neurons and Triggers Gut Dysfunction via Macrophage Recruitment.
Abstract
Herpes Simplex Virus type 1 (HSV-1), a neurotropic pathogen widespread in human population, infects the enteric nervous system (ENS) in humans and rodents and causes intestinal neuromuscular dysfunction in rats. Although infiltration of inflammatory cells in the myenteric plexus and neurodegeneration of enteric nerves are common features of patients suffering from functional intestinal disorders, the proof of a pathogenic link with HSV-1 is still unsettled mainly because the underlying mechanisms are largely unknown. In this study we demonstrated that following intragastrical administration HSV-1 infects neurons within the myenteric plexus resulting in functional and structural alterations of the ENS. By infecting mice with HSV-1 replication-defective strain we revealed that gastrointestinal neuromuscular anomalies were however independent of viral replication. Indeed, enteric neurons exposed to UV-inactivated HSV-1 produced monocyte chemoattractant protein-1 (MCP-1/CCL2) to recruit activated macrophages in the longitudinal muscle myenteric plexus. Infiltrating macrophages produced reactive oxygen and nitrogen species and directly harmed enteric neurons resulting in gastrointestinal dysmotility. In HSV-1 infected mice intestinal neuromuscular dysfunctions were ameliorated by in vivo administration of (i) liposomes containing dichloromethylene bisphosphonic acid (clodronate) to deplete tissue macrophages, (ii) CCR2 chemokine receptor antagonist RS504393 to block the CCL2/CCR2 pathway, (iii) Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) and AR-C 102222 to quench production of nitrogen reactive species produced via iNOS. Overall these data demonstrate that HSV-1 infection makes enteric neurons recruit macrophages via production of a specific chemoattractant factor. The resulting inflammatory reaction is mandatory for intestinal dysmotility. These findings provide insights into the neuro-immune communication that occurs in the ENS following HSV-1 infection and allow recognition of an original pathophysiologic mechanism underlying gastrointestinal diseases as well as identification of novel therapeutic targets.
KEYWORDS:
enteric neuropathies; inflammation; macrophage recruitment; neuromuscular dysfunction; neurotropic virus
Front Cell Infect Microbiol. 2018 Mar 15;8:74. doi: 10.3389/fcimb.2018.00074. eCollection 2018.
Brun P1, Qesari M2, Marconi PC3, Kotsafti A4, Porzionato A5, Macchi V5, Schwendener RA6, Scarpa M4, Giron MC2, Palù G1, Calistri A1, Castagliuolo I1.
Author information
1 Department of Molecular Medicine, University of Padova, Padova, Italy. 2 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy. 3 Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy. 4 Esophageal and Digestive Tract Surgery Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy. 5 Department of Neurosciences, University of Padova, Padova, Italy. 6 Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
Resource:
https://www.ncbi.nlm.nih.gov/pubmed/29600197
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