Interleukin-10 Prevents Pathological Microglia Hyperactivation following Peripheral Endotoxin Challenge
Open accessAbstract
Microglia, the resident macrophages of the brain parenchyma, are key players in central nervous system (CNS) development, homeostasis, and disorders. Distinct brain pathologies seem associated with discrete microglia activation modules. How microglia regain quiescence following challenges remains less understood. Here, we explored the role of the interleukin-10 (IL-10) axis in restoring murine microglia homeostasis following a peripheral endotoxin challenge. Specifically, we show that lipopolysaccharide (LPS)-challenged mice harboring IL-10 receptor-deficient microglia displayed neuronal impairment and succumbed to fatal sickness. Addition of a microglial tumor necrosis factor (TNF) deficiency rescued these animals, suggesting a microglia-based circuit driving pathology. Single cell transcriptome analysis revealed various IL-10 producing immune cells in the CNS, including most prominently Ly49D+ NK cells and neutrophils, but not microglia. Collectively, we define kinetics of the microglia response to peripheral endotoxin challenge, including their activation and robust silencing, and highlight the critical role of non-microglial IL-10 in preventing deleterious microglia hyperactivation.
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
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?
Clonal hematopoiesis (CH) prominently involves variants of epigenetic regulatory genes, such as DNMT3A and TET2.
“CH prominently involves variants of epigenetic regulatory genes, such as DNMT3A and TET2, which constitute an increased risk for hematologic malignancies, cardiovascular events and stroke 34,45,70,71 .”
From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [71]
The supplied passages discuss chromatin analysis and microglial responses, not clonal hematopoiesis. Searches for clonal hematopoiesis, DNMT3A, TET2, and epigenetic regulatory genes found no passage addressing the attributed claim; no page numbers were available in the returned passages. (LLM, conf=0.72)
Experimental — accuracy not yet measuredCH variants such as DNMT3A and TET2 constitute an increased risk for hematologic malignancies, cardiovascular events and stroke.
“CH prominently involves variants of epigenetic regulatory genes, such as DNMT3A and TET2, which constitute an increased risk for hematologic malignancies, cardiovascular events and stroke 34,45,70,71 .”
From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [71]
The Discussion passages concern microglial responses to endotoxin and IL-10 signaling, not clonal hematopoiesis. Searches for DNMT3A, TET2, clonal hematopoiesis, malignancy, cardiovascular risk, and stroke found no passage in our copy addressing the attributed claim; page numbers were not available. (LLM, conf=0.75)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Integrating single-cell transcriptomic data across different conditions, technologies, and species
Butler, A., Hoffman, P., Smibert, P., Papalexi, E., & Satija, R. (2018) · Nature Biotechnology · doi:10.1038/nbt.4096 · Cited by 13,174 · see citing works
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 · see citing works
Fate Mapping Reveals Origins and Dynamics of Monocytes and Tissue Macrophages under Homeostasis
Yona, S., Kim, K.-W., Wolf, Y., Mildner, A., Varol, D., Breker, M., Strauss-Ayali, D., Viukov, S., Guilliams, M., Misharin, A., et al. (2013) · Immunity · doi:10.1016/j.immuni.2012.12.001 · Cited by 3,245 · see citing works
Self-citationKrasemann, 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 · see citing works
Identification of a unique TGF-β–dependent molecular and functional signature in microglia
Butovsky, O., Jedrychowski, M. P., Moore, C. S., Cialic, R., Lanser, A. J., Gabriely, G., Koeglsperger, T., Dake, B., Wu, P. M., Doykan, C. E., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3599 · Cited by 2,543 · see citing works
Microglia development follows a stepwise program to regulate brain homeostasis
Matcovitch-Natan, O., Winter, D. R., Giladi, A., Vargas Aguilar, S., Spinrad, A., Sarrazin, S., Ben-Yehuda, H., David, E., Zelada González, F., Perrin, P., et al. (2016) · Science · doi:10.1126/science.aad8670 · Cited by 1,180 · see citing works
Van Hove, H., Martens, L., Scheyltjens, I., De Vlaminck, K., Pombo Antunes, A. R., De Prijck, S., Vandamme, N., De Schepper, S., Van Isterdael, G., Scott, C. L., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0393-4 · Cited by 1,160 · see citing works
Self-citationMicroglial signatures and their role in health and disease
Butovsky, O., & Weiner, H. L. (2018) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0057-5 · Cited by 1,046 · see citing works
Dual microglia effects on blood brain barrier permeability induced by systemic inflammation
Haruwaka, K., Ikegami, A., Tachibana, Y., Ohno, N., Konishi, H., Hashimoto, A., Matsumoto, M., Kato, D., Ono, R., Kiyama, H., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-13812-z · Cited by 923 · see citing works
Differential roles of microglia and monocytes in the inflamed central nervous system
Yamasaki, R., Lu, H., Butovsky, O., Ohno, N., Rietsch, A. M., Cialic, R., Wu, P. M., Doykan, C. E., Lin, J., Cotleur, A. C., et al. (2014) · Journal of Experimental Medicine · doi:10.1084/jem.20132477 · Cited by 855 · see citing works
Bohlen, C. J., Bennett, F. C., Tucker, A. F., Collins, H. Y., Mulinyawe, S. B., & Barres, B. A. (2017) · Neuron · doi:10.1016/j.neuron.2017.04.043 · Cited by 676 · see citing works
Kreisel, T., Frank, M. G., Licht, T., Reshef, R., Ben-Menachem-Zidon, O., Baratta, M. V., Maier, S. F., & Yirmiya, R. (2014) · Molecular Psychiatry · doi:10.1038/mp.2013.155 · Cited by 663 · see citing works
Holtman, I. R., Raj, D. D., Miller, J. A., Schaafsma, W., Yin, Z., Brouwer, N., Wes, P. D., Möller, T., Orre, M., Kamphuis, W., et al. (2015) · Acta Neuropathologica Communications · doi:10.1186/s40478-015-0203-5 · Cited by 619 · see citing works
Srinivasan, R., Lu, T.-Y., Chai, H., Xu, J., Huang, B. S., Golshani, P., Coppola, G., & Khakh, B. S. (2016) · Neuron · doi:10.1016/j.neuron.2016.11.030 · Cited by 443 · see citing works
Detecting Activated Cell Populations Using Single-Cell RNA-Seq
Wu, Y. E., Pan, L., Zuo, Y., Li, X., & Hong, W. (2017) · Neuron · doi:10.1016/j.neuron.2017.09.026 · Cited by 438 · see citing works
Il10 Deficiency Rebalances Innate Immunity to Mitigate Alzheimer-Like Pathology
Guillot-Sestier, M.-V., Doty, K. R., Gate, D., Rodriguez, J., Leung, B. P., Rezai-Zadeh, K., & Town, T. (2015) · Neuron · doi:10.1016/j.neuron.2014.12.068 · Cited by 363 · see citing works
Imaging robust microglial activation after lipopolysaccharide administration in humans with PET
Sandiego, C. M., Gallezot, J.-D., Pittman, B., Nabulsi, N., Lim, K., Lin, S.-F., Matuskey, D., Lee, J.-Y., O’Connor, K. C., Huang, Y., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1511003112 · Cited by 356 · see citing works
Minimal penetration of lipopolysaccharide across the murine blood–brain barrier
Banks, W. A., & Robinson, S. M. (2010) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2009.09.001 · Cited by 356 · see citing works
The identity and function of microglia in neurodegeneration
Song, W. M., & Colonna, M. (2018) · Nature Immunology · doi:10.1038/s41590-018-0212-1 · Cited by 308 · see citing works
Lyons, A., Downer, E. J., Crotty, S., Nolan, Y. M., Mills, K. H. G., & Lynch, M. A. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.1781-07.2007 · Cited by 258 · see citing works
Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration
Ryu, J. K., Rafalski, V. A., Meyer-Franke, A., Adams, R. A., Poda, S. B., Rios Coronado, P. E., Pedersen, L. Ø., Menon, V., Baeten, K. M., Sikorski, S. L., et al. (2018) · Nature Immunology · doi:10.1038/s41590-018-0232-x · Cited by 213 · see citing works
Flagged first, then by citations
Research works printed but not linked: 24
- [1]1. Ajami, B. ∙ Samusik, N. ∙ Wieghofer, P. ... Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models Nat. Neurosci. 2018; 21:541-551 Crossref Scopus (227) PubMed Google Scholar
- [2]2. Anderson, W.D. ∙ Greenhalgh, A.D. ∙ Takwale, A. ... Novel Influences of IL-10 on CNS Inflammation Revealed by Integrated Analyses of Cytokine Networks and Microglial Morphology Front Cell Neurosci. 2017; 11:233 Crossref Scopus (12) PubMed Google Scholar
- [5]5. Bogdan, C. ∙ Vodovotz, Y. ∙ Nathan, C. Macrophage deactivation by interleukin 10 J. Exp. Med. 1991; 174:1549-1555 Crossref Scopus (1153) PubMed Google Scholar
- [7]7. Bok, S. ∙ Kim, Y.-E. ∙ Woo, Y. ... Hypoxia-inducible factor-1α regulates microglial functions affecting neuronal survival in the acute phase of ischemic stroke in mice Oncotarget. 2017; 8:111508-111521 Crossref Scopus (39) PubMed Google Scholar
- [8]8. Buenrostro, J.D. ∙ Giresi, P.G. ∙ Zaba, L.C. ... Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position Nat. Methods. 2013; 10:1213-1218 Crossref Scopus (4002) PubMed Google Scholar
- [9]9. Buras, J.A. ∙ Holzmann, B. ∙ Sitkovsky, M. Animal models of sepsis: setting the stage Nat. Rev. Drug Discov. 2005; 4:854-865 Crossref Scopus (675) PubMed Google Scholar
- [14]14. Chakrabarty, P. ∙ Li, A. ∙ Ceballos-Diaz, C. ... IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior Neuron. 2015; 85:519-533 Full Text Full Text (PDF) Scopus (281) PubMed Google Scholar
- [16]16. Chiu, I.M. ∙ Morimoto, E.T.A. ∙ Goodarzi, H. ... A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model Cell Rep. 2013; 4:385-401 Full Text Full Text (PDF) Scopus (491) PubMed Google Scholar
- [17]17. Cossarizza, A. ∙ Chang, H.-Y. ∙ Radbruch, A. ... Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition) Eur. J. Immunol. 2019; 49:1457-1973 Crossref Scopus (737) PubMed Google Scholar
- [18]18. Davalos, D. ∙ Ryu, J.K. ∙ Merlini, M. ... Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation Nat. Commun. 2012; 3:1227 Crossref Scopus (437) PubMed Google Scholar
- [19]19. Engelhardt, K.R. ∙ Shah, N. ∙ Faizura-Yeop, I. ... Clinical outcome in IL-10- and IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation J. Allergy Clin. Immunol. 2013; 131:825-830 Full Text Full Text (PDF) Scopus (212) PubMed Google Scholar
- [20]20. Forner, L. ∙ Larsen, T. ∙ Kilian, M. ... Incidence of bacteremia after chewing, tooth brushing and scaling in individuals with periodontal inflammation J. Clin. Periodontol. 2006; 33:401-407 Crossref Scopus (558) PubMed Google Scholar
- [21]21. Glocker, E.-O. ∙ Kotlarz, D. ∙ Boztug, K. ... Inflammatory bowel disease and mutations affecting the interleukin-10 receptor N. Engl. J. Med. 2009; 361:2033-2045 Crossref Scopus (1167) PubMed Google Scholar
- [22]22. Goldmann, T. ∙ Wieghofer, P. ∙ Müller, P.F. ... A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation Nat. Neurosci. 2013; 16:1618-1626 Crossref Scopus (528) PubMed Google Scholar
- [24]24. Gosselin, D. ∙ Link, V.M. ∙ Romanoski, C.E. ... Environment drives selection and function of enhancers controlling tissue-specific macrophage identities Cell. 2014; 159:1327-1340 Full Text Full Text (PDF) Scopus (953) PubMed Google Scholar
- [25]25. Grivennikov, S.I. ∙ Tumanov, A.V. ∙ Liepinsh, D.J. ... Distinct and nonredundant in vivo functions of TNF produced by t cells and macrophages/neutrophils: protective and deleterious effects Immunity. 2005; 22:93-104 Full Text Full Text (PDF) Scopus (299) PubMed Google Scholar
- [28]28. Hanisch, U.-K. ∙ Kettenmann, H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain Nat. Neurosci. 2007; 10:1387-1394 Crossref Scopus (2946) PubMed Google Scholar
- [29]29. Hannestad, J. ∙ Gallezot, J.-D. ∙ Schafbauer, T. ... Endotoxin-induced systemic inflammation activates microglia: [11C]PBR28 positron emission tomography in nonhuman primates Neuroimage. 2012; 63:232-239 Crossref Scopus (177) PubMed Google Scholar
- [31]31. Heinz, S. ∙ Benner, C. ∙ Spann, N. ... Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities Mol. Cell. 2010; 38:576-589 Full Text Full Text (PDF) Scopus (8008) PubMed Google Scholar
- [33]33. Houle, M. ∙ Thivierge, M. ∙ Le Gouill, C. ... IL-10 up-regulates CCR5 gene expression in human monocytes Inflammation. 1999; 23:241-251 PubMed Google Scholar
- [34]34. Jaitin, D.A. ∙ Kenigsberg, E. ∙ Keren-Shaul, H. ... Massively parallel single-cell RNA-seq for marker-free decomposition of tissues into cell types Science. 2014; 343:776-779 Crossref Scopus (1300) PubMed Google Scholar
- [35]35. Kasten, K.R. ∙ Muenzer, J.T. ∙ Caldwell, C.C. Neutrophils are significant producers of IL-10 during sepsis Biochem. Biophys. Res. Commun. 2010; 393:28-31 Crossref Scopus (112) PubMed Google Scholar
- [37]37. Kohen, R. ∙ Barlev, J. ∙ Hornung, G. ... UTAP: User-friendly Transcriptome Analysis Pipeline BMC Bioinformatics. 2019; 20:154-157 Crossref Scopus (80) PubMed Google Scholar
- [40]40. Kühn, R. ∙ Löhler, J. ∙ Rennick, D. ... Interleukin-10-deficient mice develop chronic enterocolitis Cell. 1993; 75:263-274
Cited by
Sorted by citations
Silvin, A., Uderhardt, S., Piot, C., Da Mesquita, S., Yang, K., Geirsdottir, L., Mulder, K., Eyal, D., Liu, Z., Bridlance, C., et al. (2022) · Immunity · doi:10.1016/j.immuni.2022.07.004 · Cited by 368 · see citing works
A Binary Cre Transgenic Approach Dissects Microglia and CNS Border-Associated Macrophages
Kim, J.-S., Kolesnikov, M., Peled-Hajaj, S., Scheyltjens, I., Xia, Y., Trzebanski, S., Haimon, Z., Shemer, A., Lubart, A., Van Hove, H., et al. (2021) · Immunity · doi:10.1016/j.immuni.2020.11.007 · Cited by 176 · see citing works
Self-citationChung, H.-Y., Wickel, J., Hahn, N., Mein, N., Schwarzbrunn, M., Koch, P., Ceanga, M., Haselmann, H., Baade-Büttner, C., von Stackelberg, N., et al. (2023) · Science Advances · doi:10.1126/sciadv.abq7806 · Cited by 156 · see citing works
The gut microbiome modulates the transformation of microglial subtypes
Huang, Y., Wu, J., Zhang, H., Li, Y., Wen, L., Tan, X., Cheng, K., Liu, Y., Pu, J., Liu, L., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02017-y · Cited by 111 · see citing works
Interleukin-10 deficiency exacerbates inflammation-induced tau pathology
Weston, L. L., Jiang, S., Chisholm, D., Jantzie, L. L., & Bhaskar, K. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02211-1 · Cited by 69 · see citing works
TRIM45 aggravates microglia pyroptosis via Atg5/NLRP3 axis in septic encephalopathy
Huang, X., Ye, C., Zhao, X., Tong, Y., Lin, W., Huang, Q., Zheng, Y., Wang, J., Zhang, A., & Mo, Y. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02959-8 · Cited by 60 · see citing works
Kim, J.-S., Trzebanski, S., Shin, S.-H., Schori, L., Frumer Friedman, G. R., Ilani, N. C., Kadam, A., Vicario, R., Aust, O., Bugaeva, P., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115609 · Cited by 33 · see citing works
Self-citation
- Authors
- Shemer, A., Scheyltjens, I., Frumer, G. R., Kim, J.-S., Grozovski, J., Ayanaw, S., Dassa, B., Van Hove, H., Chappell-Maor, L., Boura-Halfon, S., Leshkowitz, D., Mueller, W., Maggio, N., Movahedi, K., & Jung, S.
- Affiliations
- Weizmann Institute of Science (IL)
- Vrije Universiteit Brussel (BE)
- Tel Aviv University (IL)
- Corresponding author
- Jung, Steffen
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2020-11
- Volume
- 53
- Issue
- 5
- Pages
- 1033-1049.e7
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W3092058471
- Cited by
- 175
- References
- 21
- Citations by year
- 2026: 27 · 2025: 29 · 2024: 38 · 2023: 43 · 2022: 19 · 2021: 16 · 2020: 3
- FWCI
- 7.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion, other-oa)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- European Research Council
- International Progressive MS Alliance
- Israel Science Foundation
- Minerva Foundation
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- IL-10, endotoxin challenge, natural killer cells, neutrophils, neuroinflammation
- MeSH terms
- Animals, Brain, Cells, Cultured, Endotoxins, Intestinal Mucosa, Lipopolysaccharides, Macrophage Activation, Macrophages, Biomarkers, Immunophenotyping, Interleukin-10, Microglia, 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
