The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
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
The cited source says what the claim attributes to it.
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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
limma powers differential expression analyses for RNA-sequencing and microarray studies
Ritchie, M. E., Phipson, B., Wu, D., Hu, Y., Law, C. W., Shi, W., & Smyth, G. K. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv007 · Cited by 40,458
WGCNA: an R package for weighted correlation network analysis
Langfelder, P., & Horvath, S. (2008) · BMC Bioinformatics · doi:10.1186/1471-2105-9-559 · Cited by 27,252
Leek, J. T., Johnson, W. E., Parker, H. S., Jaffe, A. E., & Storey, J. D. (2012) · Bioinformatics · doi:10.1093/bioinformatics/bts034 · Cited by 6,231
A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease
Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T. K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.018 · Cited by 5,493
Meta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
(EADI), E. A. D. I., Lambert, J.-C., (GERAD), G. A. E. R. I. A. D., Alzheimer's Disease Genetic Consortium (ADGC), (CHARGE), C. F. H. A. A. R. I. G. E., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., et al. (2013) · Nature Genetics · doi:10.1038/ng.2802 · Cited by 4,336
Full-length RNA-seq from single cells using Smart-seq2
Picelli, S., Faridani, O. R., Björklund, Å. K., Winberg, G., Sagasser, S., & Sandberg, R. (2014) · Nature Protocols · doi:10.1038/nprot.2014.006 · Cited by 4,137
Krasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., Fanek, Z., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.08.008 · Cited by 2,979
Trained immunity: A program of innate immune memory in health and– disease
Netea, M. G., Joosten, L. A. B., Latz, E., Mills, K. H. G., Natoli, G., Stunnenberg, H. G., O’Neill, L. A. J., & Xavier, R. J. (2016) · Science · doi:10.1126/science.aaf1098 · Cited by 2,768
The immunology of stroke: from mechanisms to translation
Iadecola, C., & Anrather, J. (2011) · Nature Medicine · doi:10.1038/nm.2399 · Cited by 2,596
Mills, E. L., Kelly, B., Logan, A., Costa, A. S. H., Varma, M., Bryant, C. E., Tourlomousis, P., Däbritz, J. H. M., Gottlieb, E., Latorre, I., et al. (2016) · Cell · doi:10.1016/j.cell.2016.08.064 · Cited by 2,291
Cited by
Sorted by citations
Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission
Livingston, G., Huntley, J., Liu, K. Y., Costafreda, S. G., Selbæk, G., Alladi, S., Ames, D., Banerjee, S., Burns, A., Brayne, C., et al. (2024) · The Lancet · doi:10.1016/s0140-6736(24)01296-0 · Cited by 3,860
The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication
Silva, Y. P., Bernardi, A., & Frozza, R. L. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00025 · Cited by 3,043
“It is now widely known that 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 th…”
BackgroundDefining trained immunity and its role in health and disease
Netea, M. G., Domínguez-Andrés, J., Barreiro, L. B., Chavakis, T., Divangahi, M., Fuchs, E., Joosten, L. A. B., van der Meer, J. W. M., Mhlanga, M. M., Mulder, W. J. M., et al. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-020-0285-6 · Cited by 2,690
Self-citationMicroglia states and nomenclature: A field at its crossroads
Paolicelli, R. C., Sierra, A., Stevens, B., Tremblay, M.-E., Aguzzi, A., Ajami, B., Amit, I., Audinat, E., Bechmann, I., Bennett, M., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.10.020 · Cited by 1,973
Self-citationMicroglia Biology: One Century of Evolving Concepts
Prinz, M., Jung, S., & Priller, J. (2019) · Cell · doi:10.1016/j.cell.2019.08.053 · Cited by 1,525
Self-citationDisease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration
Deczkowska, A., Keren-Shaul, H., Weiner, A., Colonna, M., Schwartz, M., & Amit, I. (2018) · Cell · doi:10.1016/j.cell.2018.05.003 · Cited by 1,474
Astrocyte Crosstalk in CNS Inflammation
Linnerbauer, M., Wheeler, M. A., & Quintana, F. J. (2020) · Neuron · doi:10.1016/j.neuron.2020.08.012 · Cited by 989
Negative feedback control of neuronal activity by microglia
Badimon, A., Strasburger, H. J., Ayata, P., Chen, X., Nair, A., Ikegami, A., Hwang, P., Chan, A. T., Graves, S. M., Uweru, J. O., et al. (2020) · Nature · doi:10.1038/s41586-020-2777-8 · Cited by 979
Human Monocyte Subsets and Phenotypes in Major Chronic Inflammatory Diseases
Kapellos, T. S., Bonaguro, L., Gemünd, I. D., Reusch, N., Saglam, A., Hinkley, E. R., & Schultze, J. L. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02035 · Cited by 942
“In a larger consortium led by the Neher group, we recently provided evidence that a systemic immune response to LPS stimulation can lead to localized immune training in the brain (149).”
BackgroundSelf-citationA Breakdown in Metabolic Reprogramming Causes Microglia Dysfunction in Alzheimer's Disease
Baik, S. H., Kang, S., Lee, W., Choi, H., Chung, S., Kim, J.-I., & Mook-Jung, I. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.06.005 · Cited by 843
Function and therapeutic value of astrocytes in neurological diseases
Lee, H.-G., Wheeler, M. A., & Quintana, F. J. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00390-x · Cited by 662
The Role of Astrocytes in CNS Inflammation
Giovannoni, F., & Quintana, F. J. (2020) · Trends in Immunology · doi:10.1016/j.it.2020.07.007 · Cited by 681
Innate and Adaptive Immune Memory: an Evolutionary Continuum in the Host’s Response to Pathogens
Netea, M. G., Schlitzer, A., Placek, K., Joosten, L. A. B., & Schultze, J. L. (2019) · Cell Host & Microbe · doi:10.1016/j.chom.2018.12.006 · Cited by 644
Self-citationNeuroinflammation in Alzheimer disease
Heneka, M. T., van der Flier, W. M., Jessen, F., Hoozemanns, J., Thal, D. R., Boche, D., Brosseron, F., Teunissen, C., Zetterberg, H., Jacobs, A. H., et al. (2025) · Nature Reviews Immunology · doi:10.1038/s41577-024-01104-7 · Cited by 638
“They also display lineage-specific characteristics and epigenetically primed responses according to the context and previous events 82,83 .”
InfluentialSelf-citationMicroglial subtypes: diversity within the microglial community
Stratoulias, V., Venero, J. L., Tremblay, M., & Joseph, B. (2019) · The EMBO Journal · doi:10.15252/embj.2019101997 · Cited by 564
“These two types of immunological imprinting, i.e. , training and tolerance, were shown to impact on the microglial responses to subsequent disease-associated stimuli, such as b -amyloidosis or ischemia (Wendeln et al , 2018).”
Yao, Y., Jeyanathan, M., Haddadi, S., Barra, N. G., Vaseghi‐Shanjani, M., Damjanovic, D., Lai, R., Afkhami, S., Chen, Y., Dvorkin‐Gheva, A., et al. (2018) · Cell · doi:10.1016/j.cell.2018.09.042 · Cited by 535
“Based on our data and those from others, it is plausible to propose that while memory macrophages at mucosal sites are beneficial to host defense, those in non-mucosal tissues such as the brain (Wendeln et al., 2018) and vasculature (Groh et al.”
Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease
Newcombe, E. A., Camats-Perna, J., Silva, M. L., Valmas, N., Huat, T. J., & Medeiros, R. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1313-3 · Cited by 532
Determinants of resident tissue macrophage identity and function
Blériot, C., Chakarov, S., & Ginhoux, F. (2020) · Immunity · doi:10.1016/j.immuni.2020.05.014 · Cited by 507
Erny, D., Dokalis, N., Mezö, C., Castoldi, A., Mossad, O., Staszewski, O., Frosch, M., Villa, M., Fuchs, V., Mayer, A., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.10.010 · Cited by 478
Self-citationChen, C., Liao, J., Xia, Y., Liu, X., Jones, R., Haran, J., McCormick, B., Sampson, T. R., Alam, A., & Ye, K. (2022) · Gut · doi:10.1136/gutjnl-2021-326269 · Cited by 491
Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease
Depp, C., Sun, T., Sasmita, A. O., Spieth, L., Berghoff, S. A., Nazarenko, T., Overhoff, K., Steixner-Kumar, A. A., Subramanian, S., Arinrad, S., et al. (2023) · Nature · doi:10.1038/s41586-023-06120-6 · Cited by 493
MAFG-driven astrocytes promote CNS inflammation
Wheeler, M. A., Clark, I. C., Tjon, E. C., Li, Z., Zandee, S. E. J., Couturier, C. P., Watson, B. R., Scalisi, G., Alkwai, S., Rothhammer, V., et al. (2020) · Nature · doi:10.1038/s41586-020-1999-0 · Cited by 501
Immunoneuropsychiatry — novel perspectives on brain disorders
Pape, K., Tamouza, R., Leboyer, M., & Zipp, F. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0174-4 · Cited by 461
The endotoxin hypothesis of neurodegeneration
Brown, G. C. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1564-7 · Cited by 457
Dendritic cell biology and its role in tumor immunotherapy
Wang, Y., Xiang, Y., Xin, V. W., Wang, X.-W., Peng, X., Liu, X., Wang, D., Li, N., Cheng, J.-T., Lyv, Y.-N., et al. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00939-6 · Cited by 463
“These imprinting processes are epigenetically mediated and enhance or suppress subsequent inflammation, respectively [89].”
BackgroundTherapeutic targeting of trained immunity
Mulder, W. J. M., Ochando, J., Joosten, L. A. B., Fayad, Z. A., & Netea, M. G. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0025-4 · Cited by 456
Crosstalk Between Astrocytes and Microglia: An Overview
Matejuk, A., & Ransohoff, R. M. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01416 · Cited by 445
“It has been found in a mouse model of Alzheimer’s disease that peripheral immune stimulation that induces acute immune training and tolerance in the brain might influence epigenetic reprogramming in microglia (29).”
BackgroundPeripheral and central immune system crosstalk in Alzheimer disease — a research prospectus
Bettcher, B. M., Tansey, M. G., Dorothée, G., & Heneka, M. T. (2021) · Nature Reviews Neurology · doi:10.1038/s41582-021-00549-x · Cited by 427
Neuropsychiatric lupus: new mechanistic insights and future treatment directions
Schwartz, N., Stock, A. D., & Putterman, C. (2019) · Nature Reviews Rheumatology · doi:10.1038/s41584-018-0156-8 · Cited by 446
Alzheimer’s disease: insights into pathology, molecular mechanisms, and therapy
Zheng, Q., & Wang, X. (2024) · Protein & Cell · doi:10.1093/procel/pwae026 · Cited by 483
Rodent models for Alzheimer disease
Götz, J., Bodea, L., & Goedert, M. (2018) · Nature reviews. Neuroscience · doi:10.1038/s41583-018-0054-8 · Cited by 422
TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease
Yang, J., Wise, L., & Fukuchi, K.-I. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00724 · Cited by 387
“(135) reported that one-time peritoneal injection of LPS prior to brain Aβ deposition (at 3 months of age) in an AD mouse model primed microglia and exacerbated the brain Aβ load 6 months later while 4 consecutive peritoneal injections of LPS (0.”
BackgroundTranscriptional signature in microglia associated with Aβ plaque phagocytosis
Grubman, A., Choo, X. Y., Chew, G., Ouyang, J. F., Sun, G., Croft, N. P., Rossello, F. J., Simmons, R., Buckberry, S., Landin, D. V., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23111-1 · Cited by 357
Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition
Colombo, A. V., Sadler, R. K., Llovera, G., Singh, V., Roth, S., Heindl, S., Sebastian Monasor, L., Verhoeven, A., Peters, F., Parhizkar, S., et al. (2021) · eLife · doi:10.7554/elife.59826 · Cited by 354
C/EBPβ-Dependent Epigenetic Memory Induces Trained Immunity in Hematopoietic Stem Cells
de Laval, B., Maurizio, J., Kandalla, P. K., Brisou, G., Simonnet, L., Huber, C., Gimenez, G., Matcovitch-Natan, O., Reinhardt, S., David, E., et al. (2020) · Cell stem cell · doi:10.1016/j.stem.2020.01.017 · Cited by 356
Trained Immunity: Reprogramming Innate Immunity in Health and Disease
Bekkering, S., Domínguez‐Andrés, J., Joosten, L. A. B., Riksen, N. P., & Netea, M. G. (2021) · Annual Review of Immunology · doi:10.1146/annurev-immunol-102119-073855 · Cited by 360
Systemic inflammation impairs microglial Aβ clearance through NLRP3 inflammasome
Tejera, D., Mercan, D., Sanchez‐Caro, J. M., Hanan, M., Greenberg, D., Soreq, H., Latz, E., Golenbock, D., & Heneka, M. T. (2019) · The EMBO Journal · doi:10.15252/embj.2018101064 · Cited by 351
“These results are in concordance with previous reports showing that peripheral administration of LPS can increase amyloid deposition in transgenic murine models of amyloidosis (Lee et al , 2008; Joshi et al , 2014; Wendeln et al , 2018).”
Establishment, maintenance, and recall of inflammatory memory
Larsen, S. B., Cowley, C. J., Sajjath, S. M., Barrows, D., Yang, Y., Carroll, T. S., & Fuchs, E. V. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.07.001 · Cited by 327
Epigenetic regulation of macrophages: from homeostasis maintenance to host defense
Chen, S., Yang, J., Wei, Y., & Wei, X. (2019) · Cellular and Molecular Immunology · doi:10.1038/s41423-019-0315-0 · Cited by 331
“Recently, it has also been demonstrated that immune memory also occurs in tissue-resident macrophages in vivo, such as microglia.(139) The molecular mechanisms responsible for memory-like activity in macrophages have not yet been elucidated.”
BackgroundMicrobiota in neuroinflammation and synaptic dysfunction: a focus on Alzheimer’s disease
Bairamian, D., Sha, S., Rolhion, N., Sokol, H., Dorothée, G., Lemere, C. A., & Krantic, S. M. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00522-2 · Cited by 326
“This translates into microglia activation [35, 58], which is in turn associated with altered expression of phagocytosisrelated genes, including CD33, CR1 and Abca7 related to cerebral Aβ-clearance in the context of AD pathology [58].”
BackgroundSex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes
Dodiya, H. B., Kuntz, T., Shaik, S. M., Baufeld, C., Leibowitz, J., Zhang, X., Gottel, N., Zhang, X., Butovsky, O., Gilbert, J. A., et al. (2019) · Journal of Experimental Medicine · doi:10.1084/jem.20182386 · Cited by 288
“In this regard, higher levels of microbial endotoxins could affect the peripheral and central inflammatory processes as has been shown recently (Wendeln et al., 2018).”
Role of Microglia TLRs in Neurodegeneration
Fiebich, B. L., Batista, C. R. A., Saliba, S. W., Yousif, N. M., & de Oliveira, A. C. P. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00329 · Cited by 291
Inflammation and Neuro-Immune Dysregulations in Autism Spectrum Disorders
Siniscalco, D., Schultz, S. T., Brigida, A. L., & Antonucci, N. (2018) · Pharmaceuticals · doi:10.3390/ph11020056 · Cited by 306
“Given this, the immunological imprinting could enhance and sustain inflammation for a long time [73].”
BackgroundMicroglial phagocytosis of neurons in neurodegeneration, and its regulation
Butler, C. A., Popescu, A. S., Kitchener, E. J. A., Allendorf, D. H., Puigdellívol, M., & Brown, G. C. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15327 · Cited by 295
Khan, N., Downey, J., Sanz, J., Kaufmann, E., Blankenhaus, B., Pacis, A., Pernet, E., Ahmed, E. A., Cardoso, S., Nijnik, A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.09.062 · Cited by 306
Emerging roles of innate and adaptive immunity in Alzheimer’s disease
Chen, X., & Holtzman, D. M. (2022) · Immunity · doi:10.1016/j.immuni.2022.10.016 · Cited by 297
Neuroinflammation in frontotemporal dementia
Bright, F., Werry, E. L., Dobson-Stone, C., Piguet, O., Ittner, L. M., Halliday, G. M., Hodges, J. R., Kiernan, M. C., Loy, C. T., Kassiou, M., et al. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0231-z · Cited by 280
Lopez‐Rodriguez, A. B., Hennessy, E., Murray, C. L., Nazmi, A., Delaney, H. J., Healy, D., Fagan, S. G., Rooney, M., Stewart, E., Lewis, A., et al. (2021) · Alzheimer's & Dementia · doi:10.1002/alz.12341 · Cited by 293
Pan, R., Ma, J., Kong, X.-X., Wang, X., Li, S., Qi, X., Yan, Y., Cheng, J., Liu, Q., Jin, W., et al. (2019) · Science Advances · doi:10.1126/sciadv.aau6328 · Cited by 293
The Impact of Systemic Inflammation on Alzheimer’s Disease Pathology
Xie, J., Van Hoecke, L., & Vandenbroucke, R. E. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.796867 · Cited by 324
Myocardial infarction accelerates breast cancer via innate immune reprogramming
Koelwyn, G. J., Newman, A. A. C., Afonso, M. S., Solingen, C. V., Corr, E. M., Brown, E. J., Albers, K. B., Yamaguchi, N., Narke, D., Schlegel, M., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0964-7 · Cited by 277
Cytokines in CAR T Cell–Associated Neurotoxicity
Gust, J., Ponce, R. A., Liles, W. C., Garden, G. A., & Turtle, C. J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.577027 · Cited by 279
“Importantly, microglia retain memory of peripheral inflammatory stimuli by long-lasting epigenetically mediated changes in gene expression (193), which could contribute mechanistically to long-term neurologic sequelae in ICANS (8).”
BackgroundSánchez‐Ramón, S., Conejero, L., Netea, M. G., Sancho, D., Palomares, Ó., & Subiza, J. L. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02936 · Cited by 271
APOE mediated neuroinflammation and neurodegeneration in Alzheimer’s disease
Parhizkar, S., & Holtzman, D. M. (2022) · Seminars in Immunology · doi:10.1016/j.smim.2022.101594 · Cited by 255
Priming Microglia for Innate Immune Memory in the Brain
Neher, J. J., & Cunningham, C. M. (2019) · Trends in Immunology · doi:10.1016/j.it.2019.02.001 · Cited by 263
Self-citationPotential Role of Gut Microbiota in Induction and Regulation of Innate Immune Memory
Negi, S., Das, D. K., Pahari, S., Nadeem, S., & Agrewala, J. N. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02441 · Cited by 247
Cien Años de Microglía: Milestones in a Century of Microglial Research
Sierra, A., Paolicelli, R. C., & Kettenmann, H. (2019) · Trends in Neurosciences · doi:10.1016/j.tins.2019.09.004 · Cited by 244
Uncovering sex differences of rodent microglia
Han, J., Fan, Y., Zhou, K., Blomgren, K., & Harris, R. A. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02124-z · Cited by 224
Peripheral immune system in aging and Alzheimer’s disease
Cao, W., & Zheng, H. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0284-2 · Cited by 214
“Equally important is to understand whether peripheral events can imprint CNS with long-lasting alterations, a notion highlighted by the detected microglia memory formed upon peripheral LPS administrations [199].”
BackgroundHuman fetal microglia acquire homeostatic immune-sensing properties early in development
Kracht, L., Borggrewe, M., Eskandar, S., Brouwer, N., Lopes, S. M. C. D. S., Laman, J. D., Scherjon, S. A., Prins, J. R., Kooistra, S. M., & Eggen, B. J. L. (2020) · Science · doi:10.1126/science.aba5906 · Cited by 213
CXCR6 orchestrates brain CD8+ T cell residency and limits mouse Alzheimer’s disease pathology
Su, W., Saravia, J., Risch, I., Rankin, S. L., Guy, C. S., Chapman, N. M., Shi, H., Sun, Y., Anil, K. C., Li, W., et al. (2023) · Nature Immunology · doi:10.1038/s41590-023-01604-z · Cited by 222
Gehrke, N., & Schattenberg, J. M. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.02.020 · Cited by 216
Glial and myeloid heterogeneity in the brain tumour microenvironment
Andersen, B. M., Akl, C. F., Wheeler, M. A., Chiocca, E. A., Reardon, D. A., & Quintana, F. J. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00397-3 · Cited by 216
Trained immunity: adaptation within innate immune mechanisms
Domínguez‐Andrés, J., dos Santos, J. C., Bekkering, S., Mulder, W. J. M., van der Meer, J. W. M., Riksen, N. P., Joosten, L. A. B., & Netea, M. G. (2022) · Physiological Reviews · doi:10.1152/physrev.00031.2021 · Cited by 227
Transcriptional and epigenetic decoding of the microglial aging process
Li, X., Li, Y., Jin, Y., Zhang, Y., Wu, J., Xu, Z., Huang, Y., Cai, L., Gao, S., Liu, T., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00479-x · Cited by 234
“Although previous studies from our and other groups showed that microglia are able to robustly respond to LPS challenge at the 2-h timepoint 41,77,88 , microglial reactivity might not reach a peak at this time.”
Sipilä, P. N., Heikkilä, N., Lindbohm, J. V., Hakulinen, C., Vahtera, J., Elovainio, M., Suominen, S., Väänänen, A., Koskinen, A., Nyberg, S. T., et al. (2021) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(21)00144-4 · Cited by 197
Neurodegenerative Disease and the NLRP3 Inflammasome
Holbrook, J. A., Jarosz-Griffiths, H., Caseley, E. A., Reyna, S. J. L., Poulter, J. A., Williams‐Gray, C. H., Peckham, D. G., & McDermott, M. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.643254 · Cited by 201
“Using the APP23 murine AD model, which develops insoluble amyloid plaques at 6 months of age, subcutaneous injection of a low dose of LPS at 3 months of age increased the number of amyloid plaques at 6 months, whereas a 4 x dose of LPS decreased the number of plaques, confirming that peripheral immune stimuli can caus…”
MethodZhang, J., Buller, B., Zhang, Z. G., Zhang, Y., Lü, M., Rosene, D. L., Medalla, M., Moore, T. L., & Chopp, M. (2021) · Experimental Neurology · doi:10.1016/j.expneurol.2021.113895 · Cited by 196
Cerebral dysfunctions caused by sepsis during ageing
Manabe, T., & Heneka, M. T. (2022) · Nature Reviews Immunology · doi:10.1038/s41577-021-00643-7 · Cited by 191
Inflammatory memory and tissue adaptation in sickness and in health
Naik, S., & Fuchs, E. V. (2022) · Nature · doi:10.1038/s41586-022-04919-3 · Cited by 188
Microglia as Dynamic Cellular Mediators of Brain Function
Wright-Jin, E. C., & Gutmann, D. H. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.08.013 · Cited by 197
Exploiting microglial and peripheral immune cell crosstalk to treat Alzheimer’s disease
Dionisio-Santos, D. A., Olschowka, J. A., & O’Banion, M. K. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1453-0 · Cited by 184
“tone established by sequential LPS injections can lead microglia to become more tolerant of inflammatory stimuli and dampen their response [165].”
BackgroundAdaptation and memory in immune responses
Natoli, G., & Ostuni, R. (2019) · Nature Immunology · doi:10.1038/s41590-019-0399-9 · Cited by 203
Immunometabolic control of trained immunity
Riksen, N. P., & Netea, M. G. (2020) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2020.100897 · Cited by 176
Vlaminck, K. D., Hove, H. V., Kancheva, D., Scheyltjens, I., Antunes, A. R. P., Bastos, J., Vara‐Pérez, M., Ali, L., Mampay, M., Deneyer, L., et al. (2021) · Immunity · doi:10.1016/j.immuni.2022.09.005 · Cited by 169
Precision Immunotherapy for Sepsis
van Ton, A. M. P., Kox, M., Abdo, W. F., & Pickkers, P. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01926 · Cited by 167
“A recent study in mice showed that repeated subjection to systemic inflammation on consecutive days induced a brain-specific training effect initially, followed by reduced immunological response (immune tolerance) of the brain after successive stimuli (85).”
BackgroundMicroglia and lipids: how metabolism controls brain innate immunity
Chausse, B., Kakimoto, P. A., & Kann, O. (2021) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2020.08.001 · Cited by 181
When encephalitogenic T cells collaborate with microglia in multiple sclerosis
Dong, Y., & Yong, V. W. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0253-6 · Cited by 169
Neuroinflammation During RNA Viral Infections
Klein, R. S., Garber, C., Funk, K. E., Salimi, H., Soung, A., Kanmogne, M., Manivasagam, S., Agner, S., & Cain, M. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042718-041417 · Cited by 160
The basis of cellular and regional vulnerability in Alzheimer’s disease
Mrdjen, D., Fox, E. J., Bukhari, S. A., Montine, K. S., Bendall, S. C., & Montine, T. J. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02054-4 · Cited by 162
Neuroinflammation: A Potential Risk for Dementia
Ahmad, M. A., Kareem, O., Khushtar, M., Akbar, M., Haque, M. R., Iqubal, A., Haider, M. F., Pottoo, F. H., Abdulla, F. S., Al-Haidar, M. B., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23020616 · Cited by 174
“Older brains maintain a level of chronic inflammation that risk losing the ability to clear the infection, as there is desensitization [32,37].”
BackgroundTrained Immunity Confers Broad-Spectrum Protection Against Bacterial Infections
Ciarlo, E., Heinonen, T., Théroude, C., Asgari, F., Roy, D. L., Netea, M. G., & Roger, T. (2019) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiz692 · Cited by 162
“Intraperitoneal injections of LPS induced epigenetic reprogramming of brain resident macrophages and modulated neuropathology in models of Alzheimer disease and stroke [42].”
BackgroundEpigenetics Control Microglia Plasticity
Cheray, M., & Joseph, B. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00243 · Cited by 157
Li, J., Wuethrich, A., Sina, A. A. I., Cheng, H., Wang, Y., Behren, A., Mainwaring, P. N., & Trau, M. (2021) · Nature Communications · doi:10.1038/s41467-021-21431-w · Cited by 158
Implications of Gut Microbiota in Neurodegenerative Diseases
Zhang, H., Chen, Y., Wang, Z., Xie, G., Liu, M., Yuan, B., Chai, H., Wang, W., & Cheng, P. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.785644 · Cited by 161
“In addition, a study reported that systemic LPS can stimulate the microglia, resulting in chronic neuroinflammation in germ-free mice (59).”
BackgroundInduction of innate immune memory: the role of cellular metabolism
Domínguez‐Andrés, J., Joosten, L. A. B., & Netea, M. G. (2018) · Current Opinion in Immunology · doi:10.1016/j.coi.2018.09.001 · Cited by 152
“Alternatively, inhibition of trained immunity could be used to counteract the excessive inflammation implicated in the pathogenesis of several diseases with an inflammatory component, such as diabetes [45], Alzheimer disease [46] or atherosclerosis [47].”
BackgroundAnalyzing microglial phenotypes across neuropathologies: a practical guide
Schwabenland, M., Brück, W., Priller, J., Stadelmann, C., Lassmann, H., & Prinz, M. (2021) · Acta Neuropathologica · doi:10.1007/s00401-021-02370-8 · Cited by 149
Self-citationTrained immunity: General and emerging concepts
Vuscan, P., Kischkel, B., Joosten, L. A. B., & Netea, M. G. (2024) · Immunological Reviews · doi:10.1111/imr.13326 · Cited by 162
“Microglia have been shown to display innate immune memory characteristics after a challenge with LPS. 126 Similarly, pre-treatment with β - glucan was shown to activate microglia without inducing significant cytokine expression and was ultimately proven to induce immune training after LPS rechallenging.”
BackgroundInfluentialExploring Sex-Related Differences in Microglia May Be a Game-Changer in Precision Medicine
Lynch, M. A. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.868448 · Cited by 146
“…differences in absorption and excretion, distribution and metabolism of drugs have been described and more adverse drug reactions have been reported in females compared with males (Whitley and Lindsey, 2009) highlighting sexual dimorphic responses to drugs, notably drugs that affect the CNS.”
BackgroundStress induced microglial activation contributes to depression
Li, B., Yang, W., Ge, T., Wang, Y., & Cui, R. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106145 · Cited by 151
Trained Immunity Carried by Non-immune Cells
Hamada, A., Torre, C., Drancourt, M., & Ghigo, É. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.03225 · Cited by 149
Neuroimmune mechanisms and therapies mediating post-ischaemic brain injury and repair
Shichita, T., Ooboshi, H., & Yoshimura, A. (2023) · Nature reviews. Neuroscience · doi:10.1038/s41583-023-00690-0 · Cited by 151
Alzheimer's-associated PU.1 expression levels regulate microglial inflammatory response
Pimenova, A. A., Herbinet, M., Gupta, I., Machlovi, S. I., Bowles, K. R., Marcora, E., & Goate, A. M. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105217 · Cited by 120
Microglia in Alzheimer's Disease: Risk Factors and Inflammation
Katsumoto, A., Takeuchi, H., Takahashi, K., & Tanaka, F. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00978 · Cited by 140
“Regarding the change in microglial phenotypes, immune memory in microglia has been shown to modify Aβ pathology in AD mice (18), in which repeated stimulation shift from inflammatory to phagocytic microglia by differential epigenetic reprogramming.”
BackgroundExtracellular vesicles and particles impact the systemic landscape of cancer
Lucotti, S., Kenific, C. M., Zhang, H., & Lyden, D. C. (2022) · The EMBO Journal · doi:10.15252/embj.2021109288 · Cited by 145
Chronic inflammation in multiple sclerosis - seeing what was always there
Matthews, P. M. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0240-y · Cited by 128
Transcriptional and Epigenetic Regulation of Microglia in Health and Disease
Yeh, H., & Ikezu, T. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.11.004 · Cited by 135
The endotoxin hypothesis of Alzheimer’s disease
Brown, G. C., & Heneka, M. T. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00722-y · Cited by 148
“Moreover, the response to LPS depends on the concentration and time course of administration as prior exposure to LPS can either sensitise or desensitise to subsequent LPS or pathology (Bahador & Cross 2007; Wendeln et al. 2018).”
BackgroundAlveolar and lung interstitial macrophages: Definitions, functions, and roles in lung fibrosis
Shi, T., Denney, L., An, H., Ho, L., & Zheng, Y. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.3ru0720-418r · Cited by 146
Planas, A. M. (2024) · Glia · doi:10.1002/glia.24501 · Cited by 144
“Induction of brain ischemia 10 month after systemic LPS administration led to either the development of a trained immune response (single LPS dose) or tolerance (repeated LPS doses) (Wendeln et al., 2018).”
Background
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
