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Annual Review of Biomedical Engineering

Volume 27, 2025

Neurons as Immunomodulators: From Rapid Neural Activity to Prolonged Regulation of Cytokines and Microglia

  • Levi B. Wood1 and Annabelle C. Singer1
  • Wallace H. Coulter Department of Biomedical Engineering, George W. Woodruff School of Mechanical Engineering and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA; email: [email protected], [email protected]
  • Vol. 27:55-72 (Volume publication date May 2025)
  • First published as a Review in Advance on January 13, 2025
  • Copyright © 2025 by the author(s).
    This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.

Abstract

Regulation of the brain's neuroimmune system is central to development, normal function, and disease. Neuronal communication to microglia, the primary immune cells of the brain, is well known to involve purinergic signaling mediated via ATP secretion and the cytokine fractalkine. Recent evidence shows that neurons release multiple cytokines beyond fractalkine, yet these are less studied and poorly understood. In contrast to ATP, cytokines are a class of signaling molecule that are much larger, with longer signaling and farther diffusion. We posit that neuron-expressed cytokines are an essential mechanism of neuron–microglia communication that arises as part of both normal learning and memory and in response to tissue pathology. Thus, neurons are underappreciated immunomodulatory cells that express diverse immunomodulatory signals. While neuronally sourced cytokines have been understudied, new technical advances make this a timely topic. The goal of this review is to define what is known about the cytokines expressed from neurons, how they are regulated, and the effects of these cytokines on microglia. We delineate key knowledge gaps and needs for new tools to define and analyze neuronal roles in immunomodulation. Given that cytokines are central regulators of microglial function, a broad new body of work is required to illuminate functional links between these neuronally expressed cytokines and sustained and transient microglial function.

Keyword(s): cytokines, kinases, microglia, neuroimmune system, neuroinflammation, neurons
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2025-05-01
2025-06-14
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/content/journals/10.1146/annurev-bioeng-110122-120158
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Neurons as Immunomodulators: From Rapid Neural Activity to Prolonged Regulation of Cytokines and Microglia
Annual Review of Biomedical Engineering 27, 55 (2025); https://doi.org/10.1146/annurev-bioeng-110122-120158
/content/journals/10.1146/annurev-bioeng-110122-120158
/content/journals/10.1146/annurev-bioeng-110122-120158
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