Abstract

Acute spinal cord injury (SCI) causes systemic immunosuppression and life-threatening infections, thought to result from noradrenergic overactivation and excess glucocorticoid release via hypothalamus–pituitary–adrenal axis stimulation. Instead of consecutive hypothalamus–pituitary–adrenal axis activation, we report that acute SCI in mice induced suppression of serum norepinephrine and concomitant increase in cortisol, despite suppressed adrenocorticotropic hormone, indicating primary (adrenal) hypercortisolism. This neurogenic effect was more pronounced after high-thoracic level (Th1) SCI disconnecting adrenal gland innervation, compared with low-thoracic level (Th9) SCI. Prophylactic adrenalectomy completely prevented SCI-induced glucocorticoid excess and lymphocyte depletion but did not prevent pneumonia. When adrenalectomized mice were transplanted with denervated adrenal glands to restore physiologic glucocorticoid levels, the animals were completely protected from pneumonia. These findings identify a maladaptive sympathetic-neuroendocrine adrenal reflex mediating immunosuppression after SCI, implying that therapeutic normalization of the glucocorticoid and catecholamine imbalance in SCI patients could be a strategy to prevent detrimental infections.

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Acknowledgements

We thank P. Popovich for critically reading the manuscript and insightful suggestions. We are grateful for the excellent technical help of D. Brandl, L. Mosch, C. Josties and I. Przesdzing. This work has been supported by grants from the German Academic Exchange Service (DAAD, D/10/43923) and German Research Foundation (DFG, PR 1274/2-1 to H.P.; STU 528/1-1, CRC-914 to S.S. and Cluster of Excellence NeuroCure to U.D.), by the Wings for Life Spinal Cord Research Foundation (WfL-DE-006/12), Else Kröner Fresenius Stiftung, German legal accident insurance (DGUV), the Era-Net-NEURON Program of the European Union, NIDILRR (#90SI5020), the Ohio State University Discovery Theme and the W.E. Hunt & C.M. Curtis Endowment to J.M.S. The National Spinal Cord Injury Database (NSCID) is funded by the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR, Grant number 90DP0083), US Department of Health and Human Services. This work was supported by the HMS Center for Immune Imaging and NIH grants AI112521 and AR068383 (to U.H.v.A.).

Author information

Author notes

    • Ulrich H von Andrian
    •  & Jan M Schwab

    These authors contributed equally to this work.

Affiliations

  1. Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, Massachusetts, USA.

    • Harald Prüss
    • , Aude Thiriot
    • , Lydia Lynch
    • , Scott M Loughhead
    • , Susanne Stutte
    • , Irina B Mazo
    •  & Ulrich H von Andrian
  2. Department of Neurology and Experimental Neurology, Clinical and Experimental Spinal Cord Injury Research (Neuroparaplegiology), Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

    • Harald Prüss
    • , Marcel A Kopp
    • , Benedikt Brommer
    • , Christian Blex
    • , Laura-Christin Geurtz
    • , Ulrich Dirnagl
    •  & Jan M Schwab
  3. German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.

    • Harald Prüss
    •  & Ulrich Dirnagl
  4. Boston Children's Hospital, F.M. Kirby Neurobiology Center, Center for Life Science, Harvard Medical School, Boston, Massachusetts, USA.

    • Andrea Tedeschi
    •  & Benedikt Brommer
  5. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

    • Andrea Tedeschi
    •  & Frank Bradke
  6. Center for Brain and Spinal Cord Repair, Department of Neuroscience, The Neurological Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

    • Andrea Tedeschi
  7. Institute for Immunology, Biomedical Center, Ludwig-Maximilians-University Munich, Martinsried, Germany.

    • Susanne Stutte
  8. Treatment Centre for Spinal Cord Injuries, Trauma Hospital Berlin, Berlin, Germany.

    • Thomas Liebscher
    •  & Andreas Niedeggen
  9. Department of Gastroenterology, Infectiology and Rheumatology, Charité – Universitätsmedizin Berlin, Berlin, Germany.

    • Magdalena S Volz
  10. National Spinal Cord Injury Statistical Center, Department of Physical Medicine and Rehabilitation, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • Michael J DeVivo
    •  & Yuying Chen
  11. Department of Neurology and Neuroscience, Center for Brain and Spinal Cord Repair, Department of Physical Medicine and Rehabilitation, The Neurological Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

    • Jan M Schwab

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Contributions

H.P., U.H.v.A. and J.M.S. designed the research study; H.P., A. Tedeschi, L.L., A. Thiriot, S.M.L., S.S., I.B.M., M.A.K., B.B., C.B., L.-C.G., T.L., A.N., F.B., M.S.V., M.J.D. and Y.C. conducted experiments and acquired data; all authors analyzed data; H.P., A.Thiriot, U.D., U.H.v.A. and J.M.S. wrote the manuscript; all authors contributed discussion to the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ulrich H von Andrian.

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https://doi.org/10.1038/nn.4643

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