Acta Neuropathologica

, Volume 132, Issue 3, pp 391–411 | Cite as

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

  • Lisa Zondler
  • Kathrin Müller
  • Samira Khalaji
  • Corinna Bliederhäuser
  • Wolfgang P. Ruf
  • Veselin Grozdanov
  • Meinolf Thiemann
  • Katrin Fundel-Clemes
  • Axel Freischmidt
  • Karlheinz Holzmann
  • Benjamin Strobel
  • Patrick Weydt
  • Anke Witting
  • Dietmar R. Thal
  • Anika M. Helferich
  • Bastian Hengerer
  • Kay-Eberhard Gottschalk
  • Oliver Hill
  • Michael Kluge
  • Albert C. Ludolph
  • Karin M. Danzer
  • Jochen H. Weishaupt
Original Paper

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.

Keywords

Amyotrophic lateral sclerosis Monocyte Innate immunity Microglia Immunoglobulin Fc receptor 

Supplementary material

401_2016_1548_MOESM1_ESM.pdf (1.7 mb)
Supplementary material 1 (PDF 1713 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Lisa Zondler
    • 1
  • Kathrin Müller
    • 1
  • Samira Khalaji
    • 2
  • Corinna Bliederhäuser
    • 1
  • Wolfgang P. Ruf
    • 1
  • Veselin Grozdanov
    • 1
  • Meinolf Thiemann
    • 4
  • Katrin Fundel-Clemes
    • 3
  • Axel Freischmidt
    • 1
  • Karlheinz Holzmann
    • 5
  • Benjamin Strobel
    • 3
  • Patrick Weydt
    • 1
  • Anke Witting
    • 1
  • Dietmar R. Thal
    • 1
  • Anika M. Helferich
    • 1
  • Bastian Hengerer
    • 3
  • Kay-Eberhard Gottschalk
    • 2
  • Oliver Hill
    • 4
  • Michael Kluge
    • 4
  • Albert C. Ludolph
    • 1
  • Karin M. Danzer
    • 1
  • Jochen H. Weishaupt
    • 1
  1. 1.Department of NeurologyUlm UniversityUlmGermany
  2. 2.Department of Experimental PhysicsUlm UniversityUlmGermany
  3. 3.Boehringer Ingelheim Pharma GmbH & Co. KGBiberachGermany
  4. 4.Apogenix GmbHHeidelbergGermany
  5. 5.Core Facility GenomicsUlm UniversityUlmGermany

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