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  • Review Article
  • Published:

Innate immune activation in neurodegenerative disease

Nature Reviews Immunology volume 14, pages 463–477 (2014)Cite this article

Subjects

Key Points

  • Neuroinflammation is characterized by microglial and astroglial cell activation, and is frequently associated with neurodegenerative disease.

  • Aberrant or misfolded proteins can activate pattern recognition receptors that are expressed by innate immune cells of the brain, leading to neuroinflammatory responses.

  • Pro-inflammatory mediators — such as cytokines, chemokines, complement components and free radicals — can lead to functional impairments and structural changes in the brain.

  • Mutations in genes that encode innate immune proteins, such as triggering receptor expressed by myeloid cells 2 (TREM2) and CD33, may increase the risk of developing certain neurodegenerative diseases.

  • Several exogenous factors — such as midlife obesity, poor oral health or systemic inflammation — may drive the pathogenesis of neurodegenerative disease by augmenting neuroinflammation.

  • A better understanding of the innate immune mechanisms that promote neuroinflammation may enable the future development of anti-inflammatory and neuroprotective therapies for neurodegenerative diseases. These therapies have to be carefully considered, as innate immune pathways can have beneficial, as well as pathological, roles in the brain.

Abstract

The triggering of innate immune mechanisms is emerging as a crucial component of major neurodegenerative diseases. Microglia and other cell types in the brain can be activated in response to misfolded proteins or aberrantly localized nucleic acids. This diverts microglia from their physiological and beneficial functions, and leads to their sustained release of pro-inflammatory mediators. In this Review, we discuss how the activation of innate immune signalling pathways — in particular, the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome — by aberrant host proteins may be a common step in the development of diverse neurodegenerative disorders. During chronic activation of microglia, the sustained exposure of neurons to pro-inflammatory mediators can cause neuronal dysfunction and contribute to cell death. As chronic neuroinflammation is observed at relatively early stages of neurodegenerative disease, targeting the mechanisms that drive this process may be useful for diagnostic and therapeutic purposes.

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Figure 1: Beneficial and detrimental functions of microglia in the brain.
Figure 2: Risk factors for Alzheimer's disease increase innate immune activation by inducing local or systemic inflammation.
Figure 3: Mechanisms of microglial cell activation in response to misfolded or aggregated proteins.

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Acknowledgements

The authors' work was supported by grants to M.T.H. and E.L. from the German Research Council (Deutsche Forschungsgemeinschaft, KFO177 and Cluster of Excellence “Immunosensation”).

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Authors and Affiliations

  1. Department of Neurology, Clinical Neuroscience, University of Bonn, Sigmund-Freud-Strasse 25, Bonn, 53127, Germany

    Michael T. Heneka & Markus P. Kummer

  2. Department of Internal Medicine, University of Massachusetts, Worcester, 01605, Massachusetts, USA

    Michael T. Heneka & Eicke Latz

  3. German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, Bonn, 53175, Germany

    Michael T. Heneka & Eicke Latz

  4. Institute of Innate Immunity, University of Bonn, Sigmund-Freud-Strasse 25, Bonn, 53127, Germany

    Eicke Latz

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Heneka, M., Kummer, M. & Latz, E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol 14, 463–477 (2014). https://doi.org/10.1038/nri3705

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