The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index.
Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1β and anti-inflammatory IL-10 cytokines
Open accessAbstract
In the elderly, systemic infection is associated with an increased frequency of behavioral and cognitive complications. We have reported that peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) causes an exaggerated neuroinflammatory response and prolonged sickness/depressive-like behaviors in aged BALB/c mice. Therefore, the purpose of this study was to determine the degree to which LPS-induced neuroinflammation was associated with microglia-specific induction of neuroinflammatory mediators. Here, we show that peripheral LPS challenge caused a hyperactive microglial response in the aged brain associated with higher induction of inflammatory IL-1beta and anti-inflammatory IL-10. LPS injection caused a marked induction of mRNA expression of both IL-1beta and IL-10 in the cortex of aged mice compared to adults. In the next set of studies, microglia (CD11b(+)/CD45(low)) were isolated from the brain of adult and aged mice following experimental treatments. An age-dependent increase in major histocompatibility complex (MHC) class II mRNA and protein expression was detected in microglia. Moreover, peripheral LPS injection caused a more pronounced increase in IL-1beta, IL-10, Toll-like receptor (TLR)-2, and indoleamine 2,3-dioxygenase (IDO) mRNA levels in microglia isolated from aged mice than adults. Intracellular cytokine protein detection confirmed that peripheral LPS caused the highest increase in IL-1beta and IL-10 levels in microglia of aged mice. Finally, the most prominent induction of IL-1beta was detected in MHC II(+) microglia from aged mice. Taken together, these findings provide novel evidence that age-associated priming of microglia plays a central role in exaggerated neuroinflammation induced by activation of the peripheral innate immune system.
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?
In the citing paper
“Indeed, increased intestinal inflammation driven by either LPS or bacterial infection correlates with elevated levels of microglial activation and release of pro-inflammatory cytokines (Riazi et al., 2008; Henry et al., 2009).”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Henry et al., 2009
In the citing paper
“In both humans [62] and mice [52,63,64], aged microglia adopt a pro-inflammatory profile including higher expression of genes including TNFα, IL-6, and IL-1β, as well as markers of ‘priming’ such as CD11b and MHC-II (Figure 1).”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [63]
In the citing paper
“Subsequent studies showed that the excessive IL-1β protein produced in the aged brain after LPS challenge was derived from the primed (MHCII positive) microglia (Henry et al, 2009).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Henry et al, 2009
In the citing paper
“Although IL-10 expression may indicate a compensatory step against the pro-inflammatory response, IL-1β production in aged mice was not attenuated despite presence of IL-10 (Henry et al, 2009).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Henry et al, 2009
In the citing paper
“It is important to note that LPS enhances expression of pro-inflammatory (eg, IL-1β) and anti-inflammatory (eg, IL-10) mediators in aged mice compared with the adult (Henry et al, 2009).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Henry et al, 2009
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
From inflammation to sickness and depression: when the immune system subjugates the brain
Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2297 · Cited by 7,395
Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005) · Science · doi:10.1126/science.1110647 · Cited by 5,827
O'Connor, J. C., Lawson, M. A., André, C., Moreau, M., Lestage, J., Castanon, N., Kelley, K. W., & Dantzer, R. (2009) · Molecular Psychiatry · doi:10.1038/sj.mp.4002148 · Cited by 1,278
Mood disorders in the medically ill: scientific review and recommendations
Evans, D. L., Charney, D. S., Lewis, L., Golden, R. N., Gorman, J. M., Krishnan, K. R. R., Nemeroff, C. B., Bremner, J. D., Carney, R. M., Coyne, J. C., et al. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.05.001 · Cited by 1,071
Gene-expression profile of the ageing brain in mice
Lee, C.-K., Weindruch, R., & Prolla, T. A. (2000) · Nature Genetics · doi:10.1038/77046 · Cited by 1,055
Interleukin-1 and neuronal injury
Allan, S. M., Tyrrell, P. J., & Rothwell, N. J. (2005) · Nature Reviews Immunology · doi:10.1038/nri1664 · Cited by 992
Godbout, J. P., Chen, J., Abraham, J., Richwine, A. F., Berg, B. M., Kelley, K. W., & Johnson, R. W. (2005) · The FASEB Journal · doi:10.1096/fj.05-3776fje · Cited by 813
Self-citationCunningham, C., Wilcockson, D. C., Campion, S., Lunnon, K., & Perry, V. H. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.2614-05.2005 · Cited by 768
Cytokine-induced sickness behavior
Kelley, K. W., Bluthé, R.-M., Dantzer, R., Zhou, J.-H., Shen, W.-H., Johnson, R. W., & Broussard, S. R. (2003) · Brain, Behavior, and Immunity · doi:10.1016/s0889-1591(02)00077-6 · Cited by 716
Innate immunity: the missing link in neuroprotection and neurodegeneration?
Nguyen, M. D., Julien, J., & Rivest, S. (2002) · Nature reviews. Neuroscience · doi:10.1038/nrn752 · Cited by 710
Microglia derived from aging mice exhibit an altered inflammatory profile
Sierra, A., Gottfried‐Blackmore, A. C., McEwen, B. S., & Bulloch, K. (2007) · Glia · doi:10.1002/glia.20468 · Cited by 688
Henry, C. J., Huang, Y., Wynne, A., Hanke, M., Himler, J., Bailey, M. T., Sheridan, J. F., & Godbout, J. P. (2008) · Journal of Neuroinflammation · doi:10.1186/1742-2094-5-15 · Cited by 678
Self-citationFord, A. L., Goodsall, A. L., Hickey, W. F., & Sedgwick, J. D. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.154.9.4309 · Cited by 631
Brain-immune communication pathways
Quan, N., & Banks, W. A. (2007) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2007.05.005 · Cited by 626 · cited 6×
“Microglia are bone marrow derived myeloid lineage cells (Simard and Rivest 2004), are interspersed throughout the CNS, and represent approximately 10-15% of the total CNS cell population.”
BackgroundInfluentialPenninx, B. W. J. H., Kritchevsky, S. B., Yaffe, K. S., Newman, A. B., Simonsick, E. M., Rubin, S. M., Ferrucci, L., Harris, T. B., & Pahor, M. (2003) · Biological Psychiatry · doi:10.1016/s0006-3223(02)01811-5 · Cited by 530
Microglia Biology in Health and Disease
Garden, G. A., & Möller, T. (2006) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-006-9015-5 · Cited by 511
Guillemin, G. J., Smythe, G., Takikawa, O., & Brew, B. J. (2005) · Glia · doi:10.1002/glia.20090 · Cited by 497 · cited 13×
“Because IDO mRNA was undetected in saline treated mice, IDO fold change was expressed relative to the IDO mRNA levels in LPS treated adults.”
BackgroundInfluentialUnderstanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response
MURRAY, P. (2006) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2006.01.010 · Cited by 436
The impact of systemic infection on the progression of neurodegenerative disease
Perry, V. H., Newman, T. A., & Cunningham, C. (2003) · Nature Reviews Neuroscience · doi:10.1038/nrn1032 · Cited by 428
Chen, J., Buchanan, J. B., Sparkman, N. L., Godbout, J. P., Freund, G. G., & Johnson, R. W. (2007) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2007.08.014 · Cited by 407
Self-citationNair, A., & Bonneau, R. H. (2006) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2005.09.012 · Cited by 392
Altered antigen expression of microglia in the aged rodent CNS
Perry, V. H., Matyszak, M. K., & Fearn, S. (1993) · Glia · doi:10.1002/glia.440070111 · Cited by 364
Simard, A. R., & Rivest, S. (2004) · The FASEB Journal · doi:10.1096/fj.04-1517fje · Cited by 362
Peripheral infection and aging interact to impair hippocampal memory consolidation
Barrientos, R. M., Higgins, E. A., Biedenkapp, J. C., Sprunger, D. B., Wright-Hardesty, K. J., Watkins, L. R., Rudy, J. W., & Maier, S. F. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.03.010 · Cited by 340
mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging
Frank, M. G., Barrientos, R. M., Biedenkapp, J. C., Rudy, J. W., Watkins, L. R., & Maier, S. F. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.03.013 · Cited by 327
Increased interleukin-6 expression by microglia from brain of aged mice
Ye, S.-M., & Johnson, R. W. (1999) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(98)00217-3 · Cited by 326
Godbout, J. P., Moreau, M., Lestage, J., Chen, J., Sparkman, N. L., Connor, J. O., Castanon, N., Kelley, K. W., Dantzer, R., & Johnson, R. W. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301649 · Cited by 299
Self-citationThe age-related attenuation in long-term potentiation is associated with microglial activation
Griffin, R., Nally, R., Nolan, Y., McCartney, Y., Linden, J., & Lynch, M. A. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04165.x · Cited by 282
Brightbill, H. D., Plevy, S. E., Modlin, R. L., & Smale, S. T. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.4.1940 · Cited by 267
Nguyen, M. D., D'Aigle, T., Gowing, G., Julien, J.-P., & Rivest, S. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.4786-03.2004 · Cited by 248
Isolation of murine microglial cells for RNA analysis or flow cytometry
Cardona, A. E., Huang, D., Sasse, M. E., & Ransohoff, R. M. (2006) · Nature Protocols · doi:10.1038/nprot.2006.327 · Cited by 236
Microglial Expression of MHC Class II Increases in Normal Aging of Nonhuman Primates
Sheffield, L. G., & Berman, N. E. J. (1998) · Neurobiology of Aging · doi:10.1016/s0197-4580(97)00168-1 · Cited by 234
Cells expressing the NG2 antigen contact nodes of Ranvier in adult CNS white matter
Butt, A. M., Duncan, A., Hornby, M. F., Kirvell, S. L., Hunter, A., Levine, J. M., & Berry, M. (1999) · Glia · doi:10.1002/(sici)1098-1136(199903)26:1 · Cited by 228
Huang, Y., Henry, C. J., Dantzer, R., Johnson, R. W., & Godbout, J. P. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.04.012 · Cited by 226
Self-citationAge and neuroinflammation: a lifetime of psychoneuroimmune consequences
Godbout, J. P., & Johnson, R. W. (2009) · Immunology and Allergy Clinics of North America · doi:10.1016/j.iac.2009.02.007 · Cited by 224
Self-citationIncreased microglial activation and protein nitration in white matter of the aging monkey☆
Sloane, J. A., Hollander, W., Moss, M. B., Rosene, D. L., & Abraham, C. R. (1999) · Neurobiology of Aging · doi:10.1016/s0197-4580(99)00066-4 · Cited by 208
Ye, S.-M., & Johnson, R. W. (2001) · Neuroimmunomodulation · doi:10.1159/000049025 · Cited by 203
EVIDENCE FOR AN EARLY INFLAMMATORY RESPONSE IN THE CENTRAL NERVOUS SYSTEM OF MICE WITH SCRAPIE
Betmouni, S., Perry, V. H., & Gordon, J. L. (1996) · Neuroscience · doi:10.1016/0306-4522(96)00212-6 · Cited by 196
The mosaic of brain glial hyperactivity during normal ageing and its attenuation by food restriction
Morgan, T. E., Xie, Z., Goldsmith, S., Yoshida, T., Lanzrein, A.-S., Stone, D., Rozovsky, I., Perry, G., Smith, M. A., & Finch, C. E. (1999) · Neuroscience · doi:10.1016/s0306-4522(98)00334-0 · Cited by 195
Kelly, A. M., Vereker, E., Nolan, Y. M., Brady, M., Barry, C. E., Loscher, C. E., Mills, K. H. G., & Lynch, M. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301938200 · Cited by 182
Effects of ageing on microglia in the normal rat brain: immunohistochemical observations
Ogura, K., Ogawa, M., & Yoshida, M. (1994) · Neuroreport · doi:10.1097/00001756-199406020-00016 · Cited by 181
Central injection of IL-10 antagonizes the behavioural effects of lipopolysaccharide in rats
Bluthé, R.-M., Castanon, N., Pousset, F., Bristow, A., Ball, C., Lestage, J., Michaud, B., KELLEY, K. W., & Dantzer, R. (1999) · Psychoneuroendocrinology · doi:10.1016/s0306-4530(98)00077-8 · Cited by 179
Signatures of hippocampal oxidative stress in aged spatial learning-impaired rodents
Nicolle, M. M., Gonzalez, J., Sugaya, K., Baskerville, K. A., Bryan, D., Lund, K. C., Gallagher, M., & McKinney, M. (2001) · Neuroscience · doi:10.1016/s0306-4522(01)00374-8 · Cited by 178
Innate immune receptor expression in normal brain aging
Letiembre, M., Hao, W., Liu, Y., Walter, S., Mihaljevic, I., Rivest, S., Hartmann, T., & Fassbender, K. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.01.004 · Cited by 175
Frank, M. G., Wieseler‐Frank, J., Watkins, L. R., & Maier, S. F. (2005) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2005.06.026 · Cited by 164
Nikodémová, M., Watters, J. J., Jackson, S. J., Yang, S. K., & Duncan, I. D. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611907200 · Cited by 159
Murray, C. A., & Lynch, M. A. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.20.12161 · Cited by 157
Inflammatory processes in the aging mouse brain: Participation of dendritic cells and T-cells
Stichel, C. C., & Luebbert, H. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.07.022 · Cited by 151
Molecular basis of age-associated cytokine dysregulation in LPS-stimulated macrophages
Chelvarajan, R. L., Liu, Y., Popa, D., Getchell, M. L., Getchell, T. V., Stromberg, A. J., & Bondada, S. (2006) · Journal of Leukocyte Biology · doi:10.1189/jlb.0106024 · Cited by 151
Lynch, A. M., Walsh, C., Delaney, A., Nolan, Y. M., Campbell, V. A., & Lynch, M. A. (2004) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.02157.x · Cited by 150
Interleukin (IL)-10 inhibits IL-6 production in microglia by preventing activation of NF-κB
Heyen, J. R. R., Ye, S.-M., Finck, B. N., & Johnson, R. W. (2000) · Molecular Brain Research · doi:10.1016/s0169-328x(00)00042-5 · Cited by 146
Basak, C., Pathak, S. K., Bhattacharyya, A., Mandal, D., Pathak, S., & Kundu, M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m412820200 · Cited by 144
Chelvarajan, R. L., Collins, S. M., Van Willigen, J. M., & Bondada, S. (2005) · Journal of Leukocyte Biology · doi:10.1189/jlb.0804449 · Cited by 141
Age and Neuroinflammation: A Lifetime of Psychoneuroimmune Consequences
Godbout, J. P., & Johnson, R. W. (2006) · Neurologic Clinics · doi:10.1016/j.ncl.2006.03.010 · Cited by 123
Self-citationLiu, Y., Chen, C.-C., Tseng, H.-P., & Chang, W. (2006) · Cellular Signalling · doi:10.1016/j.cellsig.2005.12.001 · Cited by 103
Macrosialin increases during normal brain aging are attenuated by caloric restriction
Wong, A. M., Patel, N. V., Patel, N. K., Wei, M., Morgan, T. E., de Beer, M. C., de Villiers, W. J. S., & Finch, C. E. (2005) · Neuroscience Letters · doi:10.1016/j.neulet.2005.07.058 · Cited by 85 · cited 2×
“Moreover, increased expression of scavenger receptors (Godbout et al. 2005; Wong et al. 2005), integrins (Perry et al. 1993; Stichel and Luebbert 2007), Toll-like-Receptors (Letiembre et al. 2007), and astrocytic markers (Godbout et al. 2005; Lee et al. 2000; Morgan et al. 1999) are also detected…”
Backgroundα-Tocopherol attenuates lipopolysaccharide-induced sickness behavior in mice
Berg, B. M., Godbout, J. P., Kelley, K. W., & Johnson, R. W. (2003) · Brain Behavior and Immunity · doi:10.1016/s0889-1591(03)00113-2 · Cited by 83
Self-citationAging sensitizes mice to behavioral deficits induced by central HIV-1 gp120
Abraham, J., Jang, S., Godbout, J. P., Chen, J., Kelley, K. W., Dantzer, R., & Johnson, R. W. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.11.002 · Cited by 74
Self-citationIncreased IL-1β in cortex of aged rats is accompanied by downregulation of ERK and PI-3 kinase
Maher, F. O., Martin, D. S. D., & Lynch, M. A. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2003.08.007 · Cited by 73
do Amaral, M. E. C., Barbuio, R., Milanski, M., Romanatto, T., Barbosa, H. C. L., Nadruz, W., Bértolo, M. B., Boschero, A. C., Saad, M. J. A., Franchini, K. G., et al. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03857.x · Cited by 66
Lack of an effect of vitamin E on lifespan of mice
Morley, A. A., & Trainor, K. J. (2001) · Biogerontology · doi:10.1023/a:1011589218219 · Cited by 64
Analysis of Microglial Gene Expression
Carson, M. J., Thrash, J. C., & Lo, D. D. (2004) · American Journal of PharmacoGenomics · doi:10.2165/00129785-200404050-00005 · Cited by 36
Henry, C. J., Huang, Y., Dantzer, R., Johnson, R. W., & Godbout, J. P. (2007) · The Journal of Immunology · Cited by 7
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Neuroinflammation: The Devil Is in the Details
DiSabato, D. J., Quan, N., & Godbout, J. P. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13607 · Cited by 1,640
Self-citationImmune system to brain signaling: Neuropsychopharmacological implications
Capuron, L., & Miller, A. H. (2011) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2011.01.014 · Cited by 1,195
Microglial Activation and Chronic Neurodegeneration
Lull, M. E., & Block, M. L. (2010) · Neurotherapeutics · doi:10.1016/j.nurt.2010.05.014 · Cited by 1,047
Tansey, M. G., & Goldberg, M. S. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.11.004 · Cited by 1,045
Systemic inflammation and microglial activation: systematic review of animal experiments
Hoogland, I. C. M., Houbolt, C., van Westerloo, D. J., van Gool, W. A., & van de Beek, D. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0332-6 · Cited by 957
Metadata
- Authors
- Henry, C. J., Huang, Y., Wynne, A. M., & Godbout, J. P.
- Affiliations
- The Ohio State University (US)
- Corresponding author
- Godbout, Jonathan P.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 23
- Issue
- 3
- Pages
- 309-317
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC2692986
- OpenAlex
- W2159822434
- Cited by
- 565
- References
- 63
- Citations by year
- 2026: 22 · 2025: 23 · 2024: 26 · 2023: 26 · 2022: 35 · 2021: 39 · 2020: 38 · 2019: 29 · 2018: 42 · 2017: 36 · 2016: 47 · 2015: 41 · 2014: 40 · 2013: 38 · 2012: 33
- FWCI
- 11.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG033028)
- National Institute of Mental Health (R21MH077817)
- National Institute of Allergy and Infectious Diseases (R32-AI-05-5411)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- lipopolysaccharide challenge, neuroinflammation, aging, IL-1β, IL-10, MHC class II, TLR2, indoleamine 2,3-dioxygenase, microglia, cognitive aging, depression-like behavior, systemic infection
- MeSH terms
- Aging, Analysis of Variance, Animals, Brain, Cerebral Cortex, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Injections, Intraperitoneal, Lipopolysaccharides, Male, Mice, Inbred BALB C, RNA, Messenger, Polymerase Chain Reaction, Interleukin-10, Microglia, Mice, Interleukin-1beta
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
