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Peripheral monocytes are functionally altered and invade the CNS in ALS patients

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Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease affecting primarily the upper and lower motor neurons. A common feature of all ALS cases is a well-characterized neuroinflammatory reaction within the central nervous system (CNS). However, much less is known about the role of the peripheral immune system and its interplay with CNS resident immune cells in motor neuron degeneration. Here, we characterized peripheral monocytes in both temporal and spatial dimensions of ALS pathogenesis. We found the circulating monocytes to be deregulated in ALS regarding subtype constitution, function and gene expression. Moreover, we show that CNS infiltration of peripheral monocytes correlates with improved motor neuron survival in a genetic ALS mouse model. Furthermore, application of human immunoglobulins or fusion proteins containing only the human Fc, but not the Fab antibody fragment, increased CNS invasion of peripheral monocytes and delayed the disease onset. Our results underline the importance of peripheral monocytes in ALS pathogenesis and are in agreement with a protective role of monocytes in the early phase of the disease. The possibility to boost this beneficial function of peripheral monocytes by application of human immunoglobulins should be evaluated in clinical trials.

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Acknowledgments

We thank all blood donors, healthy control probands, as well as ALS patients and pre-symptomatic mutation carriers for participation in this study. We thank all physicians at the neurologic university clinic Ulm for recruiting and taking care of the patients who have participated in this study. We thank Antje Knehr for organizing the collection of blood from members of ALS families and we thank Birgit Linkus, Tanja Wipp, Diana Wiesner, Nadine Todt, Elena Jasovskaja, Johannes Hanselmann, and Eva Barth for technical assistance. This research was supported by the Thierry Latran Foundation.

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Authors and Affiliations

  1. Department of Neurology, Ulm University, Albert-Einstein Allee 11, O25, Niveau 5, 89081, Ulm, Germany

    Lisa Zondler, Kathrin Müller, Corinna Bliederhäuser, Wolfgang P. Ruf, Veselin Grozdanov, Axel Freischmidt, Patrick Weydt, Anke Witting, Dietmar R. Thal, Anika M. Helferich, Albert C. Ludolph, Karin M. Danzer & Jochen H. Weishaupt

  2. Department of Experimental Physics, Ulm University, Ulm, Germany

    Samira Khalaji & Kay-Eberhard Gottschalk

  3. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany

    Katrin Fundel-Clemes, Benjamin Strobel & Bastian Hengerer

  4. Apogenix GmbH, Heidelberg, Germany

    Meinolf Thiemann, Oliver Hill & Michael Kluge

  5. Core Facility Genomics, Ulm University, Ulm, Germany

    Karlheinz Holzmann

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  1. Lisa Zondler
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Correspondence to Jochen H. Weishaupt.

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This work has been funded by the Thierry Latran Foundation, Grant Number: FTLAAP213/Weishaupt/innatetarget.

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The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (Ethics Committee of Ulm University) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed written consent was obtained from all individual participants included in the study prior to inclusion. All applicable international, national, and institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. All animal procedures were approved by the Regierungspräsidium Baden-Württemberg, Tübingen, Germany (No. 1090), and conducted according to the guidelines of the German Tierschutzgesetz.

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Zondler, L., Müller, K., Khalaji, S. et al. Peripheral monocytes are functionally altered and invade the CNS in ALS patients. Acta Neuropathol 132, 391–411 (2016). https://doi.org/10.1007/s00401-016-1548-y

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