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A serine protease inhibitor suppresses autoimmune neuroinflammation by activating the STING/IFN-β axis in macrophages

Cellular & Molecular Immunology volume 17, pages 1278–1280 (2020)Cite this article

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Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS). We have shown that oral administration of Bowman–Birk inhibitor (BBI), a soybean-derived serine protease inhibitor, suppresses disease in experimental autoimmune encephalomyelitis (EAE),1 a model of MS. We show here that the suppression is dependent on stimulator of interferon genes (STING) and the production of interferon-β (IFN-β) by F4/80+ macrophages. Furthermore, we show that the absence of type I IFN receptor-α (IFNAR1) in myeloid cells precludes EAE suppression by BBI, demonstrating that IFN-β signaling in these cells is relevant for the beneficial effect of BBI. BBI also induces IFN-β production by human macrophages and monocytes in a STING-dependent manner, suggesting that BBI could have a therapeutic effect in MS similar to the one in EAE.

We next investigated the cellular sources of BBI-induced IFN-β in EAE. We induced EAE in IFN-β-reporter mice that expressed YFP from the IFN-β gene and treated them with BBI at the peak of disease. By analysis of immune cells from the CNS, we observed a 3.3-fold increase (from 4.5% to 15%) in the number of YFP+ cells from BBI-treated mice compared to control mice; F4/80high macrophages (86%) were the predominant producers of IFN-β (Fig. 1b, c). In control mice, type 2 classical dendritic cells (cDCs) (98%) were the only producers of IFN-β (Fig. 1c). These data suggest that BBI acts primarily on a subset of F4/80+ macrophages present throughout the body, causing the systemic increase in IFN-β that leads to EAE suppression.

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Acknowledgements

We thank Katherine Regan for editing the manuscript. This work was supported by a grant from the National Institutes of Health (5R01AI106026) to A.R.

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Authors and Affiliations

  1. Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA

    Giacomo Casella, Javad Rasouli, Keyonna Mason, Alexandra Boehm, Daniel Hwang, Rodolfo Thome, Larissa Ishikawa, Guang-Xian Zhang, Bogoljub Ciric & Abdolmohamad Rostami

  2. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    Gaurav Kumar

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  1. Giacomo Casella
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  2. Javad Rasouli
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  3. Keyonna Mason
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Correspondence to Abdolmohamad Rostami.

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Casella, G., Rasouli, J., Mason, K. et al. A serine protease inhibitor suppresses autoimmune neuroinflammation by activating the STING/IFN-β axis in macrophages. Cell Mol Immunol 17, 1278–1280 (2020). https://doi.org/10.1038/s41423-020-0405-z

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