Dunham Jordon, van de Vis Reinofke, Bauer Jan, Wubben Jacqueline, van Driel Nikki, Laman Jon D, 't Hart Bert A, Kap Yolanda S
Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
University Groningen, University Medical Center, Department of Neuroscience, Groningen, The Netherlands.
PLoS One. 2017 Nov 14;12(11):e0188013. doi: 10.1371/journal.pone.0188013. eCollection 2017.
Oxidative stress is increasingly implicated as a co-factor of tissue injury in inflammatory/demyelinating disorders of the central nervous system (CNS), such as multiple sclerosis (MS). While rodent experimental autoimmune encephalomyelitis (EAE) models diverge from human demyelinating disorders with respect to limited oxidative injury, we observed that in a non-human primate (NHP) model for MS, namely EAE in the common marmoset, key pathological features of the disease were recapitulated, including oxidative tissue injury. Here, we investigated the presence of oxidative injury in another NHP EAE model, i.e. in rhesus macaques, which yields an acute demyelinating disease, which may more closely resemble acute disseminated encephalomyelitis (ADEM) than MS. Rhesus monkey EAE diverges from marmoset EAE by abundant neutrophil recruitment into the CNS and destructive injury to white matter. This difference prompted us to investigate to which extent the oxidative pathway features elicited in MS and marmoset EAE are reflected in the acute rhesus monkey EAE model. The rhesus EAE brain was characterized by widespread demyelination and active lesions containing numerous phagocytic cells and to a lesser extent T cells. We observed induction of the oxidative stress pathway, including injury, with a predilection of p22phox expression in neutrophils and macrophages/microglia. In addition, changes in iron were observed. These results indicate that pathogenic mechanisms in the rhesus EAE model may differ from the marmoset EAE and MS brain due to the neutrophil involvement, but may in the end lead to similar induction of oxidative stress and injury.
氧化应激越来越多地被认为是中枢神经系统（CNS）炎症/脱髓鞘疾病（如多发性硬化症（MS））中组织损伤的一个辅助因素。虽然啮齿动物实验性自身免疫性脑脊髓炎（EAE）模型在氧化损伤有限方面与人类脱髓鞘疾病不同，但我们观察到，在一种MS的非人灵长类动物（NHP）模型，即普通狨猴的EAE中，该疾病的关键病理特征得以重现，包括氧化组织损伤。在此，我们研究了另一种NHP EAE模型，即恒河猴中的氧化损伤情况，该模型会引发一种急性脱髓鞘疾病，与MS相比，它可能更类似于急性播散性脑脊髓炎（ADEM）。恒河猴EAE与狨猴EAE的不同之处在于大量中性粒细胞募集到CNS以及对白质的破坏性损伤。这种差异促使我们研究在MS和狨猴EAE中引发的氧化途径特征在急性恒河猴EAE模型中在多大程度上得到体现。恒河猴EAE脑的特征是广泛脱髓鞘以及含有大量吞噬细胞且T细胞较少的活动性病变。我们观察到氧化应激途径的诱导，包括损伤，中性粒细胞以及巨噬细胞/小胶质细胞中p22phox表达有偏好性。此外，还观察到了铁的变化。这些结果表明，由于中性粒细胞的参与，恒河猴EAE模型中的致病机制可能与狨猴EAE和MS脑不同，但最终可能导致类似的氧化应激和损伤诱导。
