Wendeln AC, Degenhardt K, Kaurani L, Gertig M, Ulas T, Jain G, Wagner J, Häsler LM, Wild K, Skodras A, Blank T, Staszewski O, Datta M, Centeno TP, Capece V, Islam MR, Kerimoglu C, Staufenbiel M, Schultze JL, Beyer M, Prinz M, Jucker M, Fischer A, Neher JJ. Innate immune memory in the brain shapes neurological disease hallmarks. Nature. 2018 Apr;556(7701):332-338. Epub 2018 Apr 11 PubMed.

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  1. Essentially, systemic immune challenges have long been assumed to affect immune function in the brain. This interesting and thorough study formally demonstrates that such challenges can have lasting effects on microglia identity and function and, importantly, correlates these effects to lasting epigenetic changes.

    One striking feature of the study is that subtly different challenges appear to cause opposite effects on certain readouts and similar effects on other readouts. For some readouts, a shorter-duration challenge leads to deviations from baseline that disappear with longer-duration challenge. Notably, injecting mice once with LPS appears to increase amyloid deposition, while injecting them four times appears to decrease amyloid deposition. This complex relationship makes extrapolating the results difficult. For example, what would be the effect of six injections or 10 injections? What if a different immune stimulus was applied rather than LPS? Would microglia enter a distinct trained state with each successive injection? The answers to such questions will be important for understanding the role of trained immunity in human neurological disease, as the systemic immune stimuli experienced by humans are diverse and innumerable.

    If the microglial-trained immune response in humans is indeed so sensitive to different degrees of stimulation, it may prove hard to target therapeutically.

    View all comments by Wilbur Song

  2. Wendeln and colleagues present an intriguing study that provides evidence for an innate immune memory in the brain. The expansion of the trained-immunity concept from the periphery to long-lived innate immune cells in the brain is a very promising step forward in our understanding of microglia biology in health and disease. In the future, it will be interesting to see which other factors in and outside of the CNS can induce trained immunity, how this is different from microglia priming, and if different factors lead to differential epigenetic reprogramming. This is of particular importance, since several risk factors, including, but not restricted to, systemic inflammation, midlife obesity, brain trauma, sedentary lifestyle, etc., share in increased innate immune activity (Heneka et al., 2015). 

    While this study identified histone marks in the complete microglia population in diseased brains of, e.g., APP23 mice, it will be interesting to see if trained immunity is a possible mechanism in the recently identified disease-associated microglia (Keren-Shaul et al., 2017). Also, it will be very important to expand this concept of innate immune memory to human brains, which could be a promising lead toward new therapeutic approaches for patients.

    References:

    Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017 Jun 15;169(7):1276-1290.e17. Epub 2017 Jun 8 PubMed.

    Heneka MT, Golenbock DT, Latz E. Innate immunity in Alzheimer's disease. Nat Immunol. 2015 Mar;16(3):229-36. PubMed.

    View all comments by Christina Ising

  3. The paper from Wendeln and colleagues highlights the complexity of innate immune responses in the context of AD and demonstrates the ability of microglia to learn and modify their behavior in response to immunological stimuli. The authors’ work represents a technical tour de force, relying on numerous unbiased global approaches to amplify our knowledge of the landscape of genes that are modulated after distinct immune challenges. As is typical with intriguing science, I found this work to be thought-provoking. I am left wondering whether the pathways that the authors uncovered are necessary or sufficient for immune training vs. tolerance. One way to answer this type of question would be to apply their tolerance/trained immunity approach to APP transgenic mice serially deficient in candidate genes.

    View all comments by Terrence Town

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