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Progranulin deficiency confers resistance to autoimmune encephalomyelitis in mice

Cellular & Molecular Immunology volume 17, pages 1077–1091 (2020)Cite this article

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Abstract

Progranulin is a secreted neurotrophin that assists in the autophagolysosomal pathways that contribute to MHC-mediated antigen processing, pathogen removal, and autoimmunity. We showed that patients with multiple sclerosis (MS) have high levels of circulating progranulin and that its depletion in a mouse model by a monoclonal antibody aggravates MS-like experimental autoimmune encephalomyelitis (EAE). However, unexpectedly, progranulin-deficient mice (Grn−/−) were resistant to EAE, and this resistance was fully restored by wild-type bone marrow transplantation. FACS analyses revealed a loss of MHC-II-positive antigen-presenting cells in Grn−/− mice and a reduction in the number of CD8+ and CD4+ T-cells along with a strong increase in the number of scavenger receptor class B (CD36+) phagocytes, suggesting defects in antigen presentation along with a compensatory increase in phagocytosis. Indeed, bone marrow-derived dendritic cells from Grn−/− mice showed stronger uptake of antigens but failed to elicit antigen-specific T-cell proliferation. An increase in the number of CD36+ phagocytes was associated with increased local inflammation at the site of immunization, stronger stimulation-evoked morphological transformation of bone marrow-derived macrophages to phagocytes, an increase in the phagocytosis of E. coli particles and latex beads and defects in the clearance of the material. Hence, the outcomes in the EAE model reflect the dichotomy of progranulin-mediated immune silencing and autoimmune mechanisms of antigen recognition and presentation, and our results reveal a novel progranulin-dependent pathway in autoimmune encephalomyelitis.

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Acknowledgements

The study was supported by the Deutsche Forschungsgemeinschaft (CRC1080, A3 to IT and MS; CRC1039 to IT) and the research funding program “Landesoffensive zur Entwicklung wissenschaftlich-ökonomischer Exzellenz” (LOEWE) of the State of Hessen, Research Center for Translational Medicine and Pharmacology, TMP. We thank Sabine Wicker for collecting blood samples from human controls and Dominique Thomas for the analysis of lipid levels in serum samples.

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Authors and Affiliations

  1. Institute of Clinical Pharmacology of the Medical Faculty, Goethe-University, Frankfurt (Main), Germany

    Katja Schmitz, Annett Wilken-Schmitz & Irmgard Tegeder

  2. Institute for Microscopic Anatomy and Neurobiology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany

    Verica Vasic & Mirko Schmidt

  3. Department of Neurology, Goethe University Hospital, Frankfurt am Main, Germany

    Robert Brunkhorst

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  1. Katja Schmitz
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Contributions

KS, VV, and AWS performed the experiments and analyzed the data. KS performed all of the in vivo and ex vivo EAE experiments. VV assessed colocalization in the cell lines. RB collected human samples and clinical data. MS contributed colocalization expertize. IT initiated the study, analyzed clinical, FACS and image data, made the figures, and created and revised the manuscript. All authors contributed to and approved the final version of the manuscript.

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Correspondence to Irmgard Tegeder.

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Schmitz, K., Wilken-Schmitz, A., Vasic, V. et al. Progranulin deficiency confers resistance to autoimmune encephalomyelitis in mice. Cell Mol Immunol 17, 1077–1091 (2020). https://doi.org/10.1038/s41423-019-0274-5

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