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Innate immune memory in the brain shapes neurological disease hallmarks
Open accessAbstract
Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished-training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer's pathology, immune training exacerbates cerebral β-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.
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“Next we tested the effect of Aβ42 and LPS on oxidative stress response in microglial cells as amyloid and inflammation trigger and exacerbate pathological changes in AD brain (Wendeln et al., 2018).”
From Alzheimer's-associated PU.1 expression levels regulate microglial inflammatory response (2021) · cites this paper as Wendeln et al., 2018
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“peripheral insults that cause a systemic inflammatory response might affect ongoing inflammation in the CNS mainly by microglial activation, production of inflammatory molecules, as well as recruitment of peripheral immune cells into the brain, thus shaping a cerebral inflammatory milieu that may seriously affect neuronal function (50, 52, 53).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [53]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, nonspecific microglia activation induced by lipopolysaccharide does not have the same amyloid-promoting effect as myelin dysfunction, as increases, decreases or no changes in amyloid burden have been reported48–51.”
From Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease (2023) · cites this paper as [49]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“A Hif1a epigenetic and transcriptomic signature was recently identified in microglia following immune training by peripheral LPS administration in APP/PS1 mice65.”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [65]
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“Animal and in-vitro studies demonstrate that inflammatory stimuli may initiate long-term priming of the microglia, peripheral CD4+ and CD8+ T cells to a proinflammatory state, (352-354) potentially increasing amyloid plaque deposition.(355)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [355]
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“Our data suggest that PU.1 may contribute to this mechanism of innate immune memory in the brain (Wendeln et al., 2018).”
From Alzheimer's-associated PU.1 expression levels regulate microglial inflammatory response (2021) · cites this paper as Wendeln et al., 2018
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In the citing paper
“although it is important to note that the efficiency of individual phagocytic processes can be dependent on experimental conditions65–67.”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [65]
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“We found little overlap between the Hif1a module reported in65 and the Hif1a regulon identified here (Supplementary Fig. 13d)”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [65]
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In the citing paper
“In healthy mice, peripherally applied LPS can differentially reprogram the epigenome of microglia by inducing either acute immune training or tolerance pending upon the number of injections [102].”
From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [102]
In the citing paper
“and systemic endotoxin precipitates brain pathology in mice expressing prions [74], APP variants [33] or TAU variants [69] or mice with α-synuclein injected in the brain [46].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [33]
In the citing paper
“Microglial markers such as purinergic receptor P2Y G-protein coupled 12 (P2ryl2), transmembrane protein 119 (Tmem119), and Fc receptor-like S, scavenger receptor (Fcrls), are used to define microglia homeostatic state.”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [11]
In the citing paper
“Whereas, inflammatory marker Clec7a is used to define microglia in neurodegenerative state [11].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [11]
In the citing paper
“Immune memory in microglia and macrophages are shaped by epigenetically mediated alterations in the enhancer repertoire of targeted genes [11, 32].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [11]
In the citing paper
“In addition, APP mice with four-time LPS treatment showed increased H3K4me1 levels in putative enhancers related to phagocytic function [11].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [11]
In the citing paper
“Cerebral beta-amyloidosis activates HIF-1a and mTOR pathways, which leads to transcriptional and functional alterations associated with increased inflammatory and immune response genes in MGnD [11].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [11]
In the citing paper
“Peripheral immune stimulation and cerebral beta-amyloidosis can lead to epigenetic modification in microglia.”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [11]
In the citing paper
“These data suggest the differential effect of immune training versus tolerance due to multiple peripheral immune stimulation, which is reflected in the epigenetic landscape of MGnD in AD mouse models.”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [11]
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“reprogrammingcouldpersistasaformof“trained”innate programming in microglia, potentially sustaining vulnerability even when canonical inflammatory triggers diminish [37, 41].”
Harnessing Microglial Repopulation: From Inflammatory Drivers to Therapeutic Allies in CNS Diseases
Li, G., Liu, H., Lan, Z., Yuan, Y. Z., Li, J. R., Dai, Z., Huang, C., He, C., Qin, S., & Su, Z. (2026) · Glia · doi:10.1002/glia.70169 · Cited by 1
“Their remarkable functional plasticity allows them to adapt to local cues, but this same plasticity becomes a liability when microglia enter a persistently activated or “primed” state (Neher and Cunningham 2019; Perry and Holmes 2014; Wendeln et al. 2018) (Figure 1).”
Glial cells in chronic inflammation: diversity, dysfunction and therapeutic targeting
Lee, H., Rone, J. M., Lee, J.-H., & Quintana, F. J. (2026) · Nature reviews. Immunology · doi:10.1038/s41577-026-01313-2 · Cited by 3
“However, other glial cell subsets can persist long after the initial inflammatory insult due to metabolic and epigenetic reprogramming, potentially sustaining chronic pathology even when the initiating stimuli have resolved 86,88,92,180 .”
Trained immunity in the treatment for haematological malignancy
Liu, Z., Chen, X., Yang, C., Wang, H., Liu, H., & Fu, R. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103210 · Cited by 1
León‐Rodríguez, A., Fernández‐Arjona, M. D. M., Pedraza, C., López‐Aranda, M. F., Visser, R., & López-Ávalos, M. D. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1828445 · Cited by 1
Metabolic and epigenetic regulation of microglia memory in neurological disorders
Wang, X., Jia, Y., Yan, X. Z., & Wang, Y. (2026) · Journal of Leukocyte Biology · doi:10.1093/jleuko/qiag085 · Cited by 1
Chen, M., Ning, J., Liu, J., Zhang, G., Xie, S., Yan, R., Yang, Y., Ren, Z., Li, X., Zhou, M. D., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1874245 · Cited by 1
“Under physiological conditions, it may enhance host defense (130).”
Bajić, D., Vučković, J., Pupovac, N., Slavić, D., Stojsic, M., Hodoba, N., Todorović, N., Plazačić, M., & Milosevic, N. P. (2026) · Medical Sciences · doi:10.3390/medsci14050536 · Cited by 1
Morton, L., Villafuerte, L. E., Garza, A. P., Lindemann, N., Wider-Eberspächer, E., Bruder, D., & Dunay, I. R. (2026) · Glia · doi:10.1002/glia.70208 · Cited by 1
“In microglia, trained immunity has been demonstrated in models of chronic stress and neuroinflammation, where initial insults prime exaggerated responses to secondary challenges (Wendeln et al. 2018; Zhang et al. 2025).”
Jyonouchi, H., & Geng, L. (2021) · IntechOpen eBooks · doi:10.5772/intechopen.95548 · Cited by 1
The Effect of Systemic Inflammation on Cognitive Function and Neurodegenerative Disease
Cunningham, C. M., & Skelly, D. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108539623.010 · Cited by 1
Pang, Y., Zhu, S., Xu, J., Su, C., Wu, B. Y., Zhang, C., & Gao, J. (2023) · Advanced Biology · doi:10.1002/adbi.202200321 · Cited by 1
Khan, H., Bhargava, V., & Elkins, K. L. (2024) · Microbiology Spectrum · doi:10.1128/spectrum.00028-24 · Cited by 1
“…bone marrow progenitors (4, 5), recent findings support the development of trained tissue resident monocytes, including microglia and alveolar macrophages (AMØs), with increased glycolytic metabolism and chemokine production; these responses are functional hallmarks of trained immunity (6–8).”
BackgroundInterplay Between Gut-microbiota and Neurodegeneration
Ashique, S., Pal, R., Kumar, S., Verma, B., Kumar, N., Kahwa, I., Farid, A., Mishra, N., Kumar, P., & Taghizadeh‐Hesary, F. (2024) · BENTHAM SCIENCE PUBLISHERS eBooks · doi:10.2174/9789815238754124010009 · Cited by 1
Guffart, E., & Prinz, M. (2024) · Advances in neurobiology · doi:10.1007/978-3-031-55529-9_3 · Cited by 1
Self-citationTLR4-mediated chronic neuroinflammation has no effect on tangle pathology in a tauopathy mouse model
Basheer, N., Muhammadi, M. K., Freites, C. L., Avila, M., Momand, M. U. D., Hryntsova, N. B., Smolek, T., Katina, S., & Žilka, N. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1468602 · Cited by 1
Acute LPS exposure enhances susceptibility to peripheral prion infection
Pal, R., Thomas, C. M., Salamat, M. K. F., Jenkins, S. J., Bradford, B. M., & Mabbott, N. A. (2025) · Scientific Reports · doi:10.1038/s41598-025-94003-3 · Cited by 1
“Independent studies and our previous data have shown that IP LPS administration can acutely affect the status of microglia and astrocytes directly within the CNS 32,55,56 .”
Quantification of Human Swiprosin-1/EFhd2 Expression on Protein and RNA Level
Fürnrohr, B. G., & Mielenz, D. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9030-6_37 · Cited by 1
Xavier, A. M., Belhocine, S., & Gosselin, D. (2019) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1449 · Cited by 1
“Wendeln et al. (2018) explored the effects of various regimen of exposure to systemic inflammatory responses in early adulthood on the development of lesions in a pre-clinical mouse model of AD (Wendeln et al., 2018).”
BackgroundPhysiopathologie et classification des neuropathies inflammatoires
Créange, A. (2021) · Bulletin de l Académie Nationale de Médecine · doi:10.1016/j.banm.2021.05.018 · Cited by 1
Desplats, P., Gutierrez, A. M., Antonelli, M. C., & Frasch, M. G. (2019) · arXiv (Cornell University) · Cited by 1
Süß, P., Hoffmann, A., Rothe, T., Baum, W., Staszewski, O., Schett, G. A., Prinz, M., Krönke, G., Glass, C. K., Winkler, J., et al. (2018) · SSRN Electronic Journal · doi:10.2139/ssrn.3263013
Self-citationAquaporin 4 is differentially increased and depolarized in association with tau and amyloid-betaPreprint
Kecheliev, V., Boss, L., Maheshwari, U., Konietzko, U., Keller, A., Razansky, D., Nitsch, R. M., Klohs, J., & Ni, R. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.04.26.489273 · Cited by 1
“Dysfunction of the glymphatic system reduces the removal of amyloid-beta (Aβ) and tau 52 proteins [16-18].”
BackgroundPedroso-Roussado, C., Guppy, F. M., Bowler, L. D., & Inácio, J. (2022) · Preprints.org · doi:10.20944/preprints202212.0205.v1
Macrophage memory: Types, Mechanisms, and Its Role in Health and DiseasePreprint
Liao, A., Fang, X.-H., Li, Z.-J., Liu, C., & Mor, G. (2023) · doi:10.22541/au.169006567.79973007/v1 · Cited by 1
Carp, T.-N. (2024) · Preprints.org · doi:10.20944/preprints202401.2108.v2
Influenza A infection accelerates disease-associated microglia formation during physiological agingPreprint
Grant, R. A., Runyan, C. E., Minogue, G., Stoolman, J. S., Watanabe, S., Chen, F., Senkow, K. J., Cusick, L., Schleck, M. J., Nafikova, R. A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.11.693336 · Cited by 1
“Some have suggested that aging may “prime” the neuroimmune system for an aberrant response to peripheral immune activation, 28–31 and enhancement of pathological hallmarks has been observed in mouse models of neurodegeneration with peripheral inflammatory stimuli 32,33 .”
Semaglutide Attenuates Neuroinflammation in MicePreprint
Belmont-Rausch, D. M., Ludwig, M. Q., Bentsen, M. A., Hansen, S. N., Secher, A., Holst, D., Moreno, J., Das, V., Egerod, K. L., Bjerregaard, A.-M., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.10.698763 · Cited by 1
“This selective suppression of pro-inflammatory factors while maintaining anti-inflammatory signaling suggests that semaglutide promotes a state of immune tolerance 39 , potentially explaining its effects on both peripheral inflammation and brain immune responses”
Cabeza‐Fernández, S., Niñerola, S., Armengol-Gomis, A., Paraíso‐Luna, J., Casillas-Bajo, Á., Gomez-Sanchez, J. A., Cabedo, H., Barco, Á., & de la Fuente, A. G. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.05.11.724385 · Cited by 1
Memorable cerebral inflammation
Attenello, F. J. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aat8525
European Molecular Biology Organization (EMBO) Workshop: Microglia 2018
Horiuchi, H. (2018) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12468
“In another unique study, Dr Wendeln suggested that the epigenetic reprograming in microglia contributes to pathology, including AD and stroke.(17) Namely, immune training and tolerance enhanced or suppressed subsequent inflammation by epigenetic reprograming.”
BackgroundRole of SHIP-1 phosphatase in trained immunity modulation
Sanz-Leal, P. (2018) · doi:10.4321/repisalud.7167
Metabolic reprogramming supports microglial survival and immune function
York, E. M. (2021) · cIRcle (University of British Columbia) · doi:10.14288/1.0379730
Modulation of immune responses by Fasciola hepatica-derived products
Walsh, R. (2019) · Arrow@dit (Dublin Institute of Technology)
Long-Lasting Memory Impairments after Subchronic Immune Challenge
Tchessalova, D. (2019) · Deep Blue (University of Michigan)
Deftu, A., & Suter, M. R. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-809324-5.24214-4
Chromatin Dynamics and Genetic Variation Combine to Regulate Innate Immune Memory.
Kim, J. S., & Ciernia, A. V. (2020) · PubMed
Datta, M., Hansen, S. M., & Staszewski, O. (2020) · J — Multidisciplinary Scientific Journal · doi:10.3390/j3040028
“Taken together with our previously reported evidence that Hdac1 and 2 function is required for microglial development, maturation and immune memory and is involved in the regulation of microglial response to amyloid deposits in an AD model [8,9], these results indicate that Hdac1 and Hdac2 function in microglia is sti…”
BackgroundResultInfluentialSelf-citationEpigenetic Biomarker and Therapeutic Intervention for Dementia
Islam, R. (2021) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-8394
Althammer, F., & Stern, J. E. (2021) · Masterclass in neuroendocrinology · doi:10.1007/978-3-030-62383-8_5
Russell, A. E. (2019) · The Research Repository @ WVU (West Virginia University) · doi:10.33915/etd.3947
Metadata
- Authors
- Wendeln, A.-C., Degenhardt, K., Kaurani, L., Gertig, M., Ulas, T., Jain, G., Wagner, J., Häsler, L. M., Wild, K., Skodras, A., Blank, T., Staszewski, O., Datta, M., Centeno, T. P., Capece, V., Islam, M. R., Kerimoglu, C., Staufenbiel, M., Schultze, J. L., Beyer, M., Prinz, M., Jucker, M., Fischer, A., & Neher, J. J.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- University of Bonn (DE)
- University of Freiburg (DE)
- Corresponding author
- Neher, Jonas J.
- ORCID
- Venue
- Nature
- Published
- 2018-04
- Volume
- 556
- Issue
- 7701
- Pages
- 332-338
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6038912
- OpenAlex
- W2796983933
- Cited by
- 956
- References
- 51
- Citations by year
- 2026: 117 · 2025: 102 · 2024: 120 · 2023: 106 · 2022: 121 · 2021: 135 · 2020: 104 · 2019: 90 · 2018: 60
- FWCI
- 43.97
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DZNE Pub (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- trained immunity, immunological imprinting, immune tolerance, microglia, epigenetic reprogramming, neuroinflammation, Alzheimer's disease, beta-amyloidosis, stroke, neuropathology
- MeSH terms
- Alzheimer Disease, Amyloidosis, Animals, Brain, Disease Models, Animal, Female, Gene Expression Regulation, Humans, Immune Tolerance, Immunity, Innate, Immunologic Memory, Inflammation, Male, Nervous System Diseases, Microglia, Stroke, Epigenesis, Genetic, Mice
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