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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.
In the citing paper
“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.
In the citing paper
“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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In the citing paper
“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 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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InfluentialZou, X., Yang, Y., Yue, B., Yang, H., Yang, Y., Li, M., Du, O., Qiao, G., Wu, Y., Du, J., et al. (2025) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.70455 · Cited by 4
“They include the recognition of pathogen-associated molecular patterns (PAMPs) by PRRs, the production of inflammatory cytokines, and the recruitment of immune cells to the site of infection [14].”
Gao, C., Lin, Z., Chen, Y., Gan, R., Wang, K., He, X., & Han, H. (2025) · Neuropharmacology and Therapy · doi:10.15212/npt-2025-0015 · Cited by 5
“The microglial epige-nome is also plastic, because it can be modified by stimuli such as inflammation and aging [36,87].”
InfluentialSmoothened-mediated signaling contributes to immune and non-immune functions of microglia
Mesaoudi, A. E., Kassoussi, A., Zahaf, A., Ayadi, M., Naglieri, S., Marie, C., Encha‐Razavi, F., Bobé, P., Martinovic, J., Parras, C. M., et al. (2025) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2025.106226 · Cited by 4
Innate Immune Tolerance Regulates Microglia Response to Aβ Oligomers
Valerio, R. R., Santos, Á. R., Nóbrega, A. H. L., Martins, R., Felice, F. G. D., Ferreira, S. T., Savino, W., Bonomo, A. C., Bernardi, A., & Frozza, R. L. (2026) · Journal of Neurochemistry · doi:10.1111/jnc.70341 · Cited by 5
“A growing body of evidence demonstrates that systemic inflammation modifies microglial activation, causes synapse dysfunction and loss, and increases brain Aβ loads (Lee et al. 2008; Go et al. 2016; Wendeln et al. 2018; Tejera et al. 2019; Knopp et al. 2022).”
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Persistent microglial activation following neonatal CMV infection mediates neurodegeneration
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Lipid Droplet-Accumulating Microglia as a Therapeutic Node in Neurodegenerative Disease
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“Trainedimmunityhasbeende fi nedasamemory-likeenhancementofinnate immune responsiveness without constitutive in fl ammatory activation 11 , and recent CNS-focused work demonstrates that immune training can restore functionalcapacityinagedmyeloidcellswithoutinducingin fl ammatorygene expression 52,53 .”
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“The immune memory of microglia can modulate neuropathology and potentially serve as a mechanism for lipopolysaccharide (LPS)-induced immune memory in the brain, with TLR4 playing a pivotal role in this phenomenon [43] both bene fi cial and detrimental effects of TLR4 in AD have been reported.”
Divergent metabolic rewiring shapes altered innate immunity
Liu, M., Wang, X., Qu, X., Wang, Y., Shen, X., & Xu, L. (2025) · Cellular Immunology · doi:10.1016/j.cellimm.2025.105025 · Cited by 6
Zhang, Q., Kong, W., Yuan, J., Chen, Q., Gong, C., Liu, L., Wang, F., Huang, J., Yang, G., Zhou, K., et al. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.639656 · Cited by 4
Microbial neuraminidase induces TLR4-dependent long-term immune priming in the brain
Fernández‐Arjona, M. D. M., León‐Rodríguez, A., Grondona, J. M., & López-Ávalos, M. D. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.945229 · Cited by 4
Association between doxycycline use and long-term functioning in patients with schizophrenia
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Pol, J. G., Lizarralde-Guerrero, M., Checcoli, A., & Kroemer, G. (2024) · OncoImmunology · doi:10.1080/2162402x.2024.2385124 · Cited by 4
The vasculature in sepsis: delivering poison or remedy to the brain?
Singer, B. H. (2019) · Journal of Clinical Investigation · doi:10.1172/jci127679 · Cited by 4
“Microglia are especially susceptible to long-term reprogramming after high-dose endotoxin exposure (11), though the balance of tolerance and priming that results from persistent exposure to proinflammatory signals over time is probably governed by a network of interactions among glia and neurons…”
BackgroundRussell, A. E., Cavendish, J. Z., Rai, A., Vannoy, M., Dakhlallah, A., Hu, H., Ren, X. S., Amer, A. O., Brown, C. M., Marsh, C. B., et al. (2021) · ASN NEURO · doi:10.1177/1759091421991769 · Cited by 4
“…formation by increasing platelet aggregation (Zeller et al., 2005; Elkind et al., 2011), and can also increase circulating cytokine concentrations (Wilson et al., 1998; Guedes et al., 2016) which has been shown to play a major role in fibronectin accumulation (Pawluczyk and Harris, 1998) and…”
BackgroundKulakauskienė, D., Narauskaitė, D., Gečys, D., Juknaitė, O., Jankauskaitė, L., Masaitytė, A., Šventoraitienė, J., Inokaitis, H., Miknienė, Z., Sadauskienė, I., et al. (2021) · Biology · doi:10.3390/biology10121359 · Cited by 5
“Recent evidence indicates that peripheral infections can stimulate an immune response in the brain, causing irreversible genetic and epigenetic changes in brain immune cells leading to the formation of immune memory [25].”
Effector-Triggered Trained Immunity: An Innate Immune Memory to Microbial Virulence Factors?
Torre, C., & Boyer, L. (2022) · Toxins · doi:10.3390/toxins14110798 · Cited by 4
“As an example, low-dose LPS—a well-known inducer of the NF-κB pathway—has been identified as an inducer of TI [35].”
Multifactorial glial responses and their contributions to Alzheimer's disease continuum
Hijioka, M., Manabe, T., & Saito, T. (2023) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12745 · Cited by 4
Wang, Y., Tang, Y., Liu, T., Shao, L., Li, C., Wang, Y., & Tan, P. (2024) · Molecular Neurobiology · doi:10.1007/s12035-023-03903-w · Cited by 4
“This trend is consistent with the literature, which may participate in immune disorders in AD patients, leading to pathological damage and cognitive impairment [42].”
Reversal of immune-cell shutdown protects the ageing brain
Neher, J. J. (2021) · Nature · doi:10.1038/d41586-021-00063-6 · Cited by 4
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“Next, we examined the impact of 243 NKCC1 deficiency on morphological characteristics of microglia after activation by endotoxin that 244 primes microglial inflammatory responses and leads to morphological transformation [52].”
BackgroundGlycation renders ɑ-synuclein oligomeric strain and modulates microglia activationPreprint
Kumari, M., Kumar, B., Bisht, K. S., & Maiti, T. K. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.01.15.476311 · Cited by 4
The Role of Circulating Aβ Seeds in the Progression of Cerebral Amyloidosis
Gamez, N., & Morales, R. (2022) · Neuroscience Insights · doi:10.1177/26331055221123072 · Cited by 4
What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease?
Brutkiewicz, R. R., Cao, W., Morgan, D., Reis, R. S. D., Suryadevara, V., Willette, A. A., Willette, S. A., Wyatt-Johnson, S. K., & Duggan, M. R. (2025) · Trends in Neurosciences · doi:10.1016/j.tins.2025.05.009 · Cited by 3
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Postoperative sepsis and its sequential impact on dementia
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“The inflammatory response in sepsis is not typically caused by direct brain infection but is instead a systemic immune response transmitted to the central nervous system through various pathways [40, 41].”
The link between early-life adversity and later alcohol use disorder: A role for microglia?
Lichtenstein, H. D., Sequeira, M. K., & Bolton, J. L. (2025) · Neurobiology of Stress · doi:10.1016/j.ynstr.2025.100714 · Cited by 3
Chowdhury, R., Hendlinger, A., Rieß, O., & Schulze-Hentrich, J. M. (2025) · Epigenomics · doi:10.1080/17501911.2025.2518909 · Cited by 3
Dual role of innate immune activation in cerebral small vessel disease
Peng, Y., Sun, Y., Song, X., Jin, C. J., Yin, X., & Zheng, X. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.115178 · Cited by 3
NR3C1 limits the imprinting of astrocyte epigenetic inflammatory memory early in life
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Paraiso, H. C., Yen, J.-H. J., Scofield, B. A., Kuo, P., Chang, F., & Yu, I.-C. I. (2025) · The FASEB Journal · doi:10.1096/fj.202501457rr · Cited by 4
“Innate immune memory in microglia has been demonstrated in recent studies, showing that microglia can update their responses to either sensitization (immune training) or desensitization (immune tolerance) reactions when encountering subsequent inflammatory insults [37, 55].”
InfluentialUemura, K., Hiro, S., Attachaipanich, S., Du, R., Yusof, N. I. S. M., Kinoshita, M., Hikosaka, M., & Ohtsuki, G. (2026) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2025.1669272 · Cited by 5
Liu, Y., Ye, Y., Fan, M., Cheng, Y., Sun, S., & Qiu, Z. (2026) · Neuron · doi:10.1016/j.neuron.2026.05.015 · Cited by 2
Narcolepsy is (not) an autoimmune disease
Vassalli, A., Tafti, M., & Liblau, R. (2026) · Nature Reviews Neurology · doi:10.1038/s41582-026-01232-9 · Cited by 3
Trained immunity links hematopoietic stem cell aging to aging-associated inflammation
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“When appropriately induced, trained immunity is protective against infection and tumors, and reinforces tissue repair upon acute damage 14,16–21 , but its maladaptation leads to chronic inflammatory pathologies and hinders tissue repair after repetitive damage 11,19,22–29 .”
Brain and immune system: KURU disease a toxicological process?
Luisetto, M., Nili-Ahmadabadi, B., Mashori, G. R., Yesvi, A., Sahu, R. K., Nasser, H., Luca, C., & Khan, F. A. (2018) · Journal of Neuroscience and Neurological Disorders · doi:10.29328/journal.jnnd.1001010 · Cited by 3
“Our results identify immune memory in the brain as an important modi ier of neuropathology [13].”
ResultPechacek, K. M., & Haar, C. V. (2022) · Physiology & Behavior · doi:10.1016/j.physbeh.2022.113998 · Cited by 3
Stress and Microglia: A Double-edged Relationship
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Barczuk, J., Galita, G., Siwecka, N., Golberg, M., Saramowicz, K., Granek, Z., Wiese, W., Majsterek, I., & Rozpędek‐Kamińska, W. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252111399 · Cited by 3
“…α in A β plaque-associated microglia has been confirmed in various in vivo AD models, and activation of HIF-1 α signaling has been proposed as a detrimental modulator of AD pathology, as enhanced or inhibited HIF-1 α signaling occurred concurrently with enhanced or attenuated A β deposition [32].”
BackgroundEpigenetic Regulation of Macrophage Polarization
Maheshwari, A., & Singh, S. (2025) · Newborn · doi:10.5005/jp-journals-11002-0118 · Cited by 3
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“Second, although medin represents a good power as a diagnostic biomarker for AD, whether medin levels could be early detected in the AD spectrum population, especially in the preclinical stage, remains unclear (Wendeln et al., 2018; Yang et al., 2022).”
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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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