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The CD24-Siglec G axis protects mice against cuprizone-induced oligodendrocyte loss: targeting danger signal for neuroprotection

Cellular & Molecular Immunology volume 15, pages 79–81 (2018)Cite this article

Oligodendrocytes play a critical role in neuroprotection by both remyelination-dependent and remyelination-independent mechanisms and confer protection in both inflammatory and degenerative diseases that involve the central nervous system, including multiple sclerosis, Alzheimer’s disease and potentially Parkinson’s disease.1, 2, 3, 4 Although accumulating data have supported a major role for inflammation in the susceptibility of oligodendrocytes to cuprizone, the molecular pathways that regulate oligodendrocyte survival have not been well established. Here, we report that the targeted mutation of either Cd24 or Siglecg, which forms an axis that selectively regulates the innate inflammatory response to danger-associated molecular patterns (DAMPs), protects mice against cuprizone-induced oligodendrocyte loss. Moreover, the systemic administration of CD24Fc, which is known to stimulate Siglec G signaling and suppress the inflammatory response in vivo, protects oligodendrocytes against chronic exposure to cuprizone. Our data suggest that the host response to cellular injury actively participates in oligodendrocyte loss and provides a new approach to maintain oligodendrocytes under pathological conditions.

Chronic exposure to cuprizone is a classical model to induce oligodendrocyte loss in rodents.5 Several groups have reported that inflammation plays a critical role in the loss of oligodendrocytes. However, the nature of the initiating signal for oligodendrocyte loss has not been clearly delineated. Janeway proposed that innate immunity is initiated primarily via the pattern recognition of microbial products called pathogen-associated molecular patterns (PAMPs).6, 7 Subsequently, Matzinger proposed a danger signal, subsequently termed DAMPs by others, as the key to initiate the innate immune response.8 We previously showed that the inflammation induced by PAMPs and DAMPs can be discriminated by the CD24-Siglec G interaction because the targeted mutation of either gene selectively enhances the host response to DAMPs without affecting that to PAMPs.9, 10 Here, we explore the potential contribution of the innate immune response to DAMPs by evaluating the impact of targeted mutations of the Cd24 or Siglecg genes on oligodendrocyte survival after chronic cuprizone treatment.

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Acknowledgements

We thank Fei Tang, Wei Wu, Xuexiang Du and Emmanuelle Jecrois for valuable advice and assistance. This study was supported by AI64350 and AG036690. The CD24Fc fusion protein was provided by OncoImmune, Inc. PZ and YL are among the co-founders of OncoImmune and have equity interest in the company.

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  1. Center for Cancer and Immunology Research, Children’s Research Institute, Children’s National Health System, Washington, 20010, DC, USA

    Ning Li, Pan Zheng & Yang Liu

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  1. Ning Li
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Correspondence to Pan Zheng or Yang Liu.

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Li, N., Zheng, P. & Liu, Y. The CD24-Siglec G axis protects mice against cuprizone-induced oligodendrocyte loss: targeting danger signal for neuroprotection. Cell Mol Immunol 15, 79–81 (2018). https://doi.org/10.1038/cmi.2017.47

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