In this case–control study, we confirmed that the concentrations of YKL-40, sCD14 and sCD163 were increased in NMO patients. Moreover, these biomarkers were all significantly associated with the severity of the disease. To our knowledge, this study reported for the first time about the changes of YKL-40, sCD14 and sCD163 levels in CSF of patients with NMO.
NMO is an autoimmune disease characterized by optic neuritis and myelitis. The exact mechanism of NMO neuronal damage is still unclear. The key factors that dominate the current speculation are microglia or macrophage activation, astrocyte damage caused by AQP4 antibodies, secondary demyelination of nerve axons, and lactic acid accumulation in damaged mitochondria. Microglia, also known as CNS macrophages, are the main immune surveillance cells in the CNS and play a key role in the process of inflammation. The most prominent feature of microglia is the rapid activation when under stress conditions such as injury, inflammation, neurodegeneration, infection and brain tumor. Microglial activation, as revealed in CSF by sCD14, sCD163 and YKL-40 have well known implications in brain diseases, such as MS, intracranial infection and neurodegenerative diseases[7, 28] .
Interleukin-6 (IL-6) and type I interferon family members, including interferon-α (IFN- α) and interferon-β (IFN- β), are classic inflammatory promoters and have been shown to be key inflammatory mediators in the pathogenesis of central nervous system inflammatory demyelinating diseases such as NMO and MS. It has also been confirmed that IL-6 is an important cytokine causing the recurrence of NMOSD. IL-6 and IFN- α can lead to the activation of microglia and participate in the regulation of microglia related inflammation. Up to now, more and more evidence shows that highly reactive microglia is a key feature of NMO[30-33].
Recent findings query the notion that microglial is functional only when the CNS in a diseased state. The current understanding is microglia not only have a simple reacting to the injury, infection or pathological state, evidence shows that microglia can repair the structure of CNS, refine regulate the connectivity of neural circuits and networks, but also play a role in the formation of nervous system plasticity. However, whether the effect of microglia activation is beneficial or harmful remains to be further clarified.
Conspicuous activation of microglia has been observed in the actively demyelinating spinal cord lesions of patients with NMOSD, considered to be one of the pathogenic mechanisms, and it is also proposed that limit the adverse effects of microglia activation as a future treatment strategy worthy for further investigation [35, 36]. And the same performance was found in animal experiments.Injection of serum IgG from NMO patients into the spinal cord or optic nerve of the experimental rats, can lead to NMO-like pathological changes, including significant activation of microglia around these lesion[37-39]. In another animal experiments, they observed that exogenous injection of patients' serum AQP4-IgG could induce marked microglial activation, and further co-immunostaining revealed that these activated microglia were in close to astrocytes in the spinal cord lesions, suggesting that microglia can phagocytose AQP4 positive astrocytes.Through the observation of these human or animal models, we found that microglia activation can directly affect the function and survival of astrocytes, as well as chemotactic highly inflammatory factors, aggravate the inflammatory response of the CNS, thus promoting the occurrence of NMOSD.
In the present study, the levels of these microglia activation markers in CSF of patients with NMO were positively correlated with EDSS scores, further clarifing that microglia activity were coincided with the severity of disease. Suggesting that YKL-40, sCD14 and sCD163 can be used to assess the severity of NMO and serve as a marker to monitor the effect of treatment and predict the prognosis of the disease.