Microglial p38α MAPK is critical for LPS-induced neuron degeneration, through a mechanism involving TNFα

Xing, Bin; Bachstetter, Adam D; Van Eldik, Linda J

doi:10.1186/1750-1326-6-84

Cited by 101Neuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and TreatmentsPain Mechanisms and Treatments

Microglial p38α MAPK is critical for LPS-induced neuron degeneration, through a mechanism involving TNFα

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Xing, Bin, Bachstetter, Adam D, Van Eldik, Linda J·2011·Molecular Neurodegeneration

DOI 10.1186/1750-1326-6-84PMC PMC3292986

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Abstract

BACKGROUND: The p38α MAPK isoform is a well-established therapeutic target in peripheral inflammatory diseases, but the importance of this kinase in pathological microglial activation and detrimental inflammation in CNS disorders is less well understood. To test the role of the p38α MAPK isoform in microglia-dependent neuron damage, we used primary microglia from wild-type (WT) or p38α MAPK conditional knockout (KO) mice in co-culture with WT cortical neurons, and measured neuron damage after LPS insult. RESULTS: We found that neurons in co-culture with p38α-deficient microglia were protected against LPS-induced synaptic loss, neurite degeneration, and neuronal death. The involvement of the proinflammatory cytokine TNFα was demonstrated by the findings that p38α KO microglia produced much less TNFα in response to LPS compared to WT microglia, that adding back TNFα to KO microglia/neuron co-cultures increased the LPS-induced neuron damage, and that neutralization of TNFα in WT microglia/neuron co-cultures prevented the neuron damage. These results using cell-selective, isoform-specific KO mice demonstrate that the p38α MAPK isoform in microglia is a key mediator of LPS-induced neuronal and synaptic dysfunction. The findings also provide evidence that a major mechanism by which LPS activation of microglia p38α MAPK signaling leads to neuron damage is through up-regulation of the proinflammatory cytokine TNFα. CONCLUSIONS: The data suggest that selective targeting of p38α MAPK signaling should be explored as a potential therapeutic strategy for CNS disorders where overproduction of proinflammatory cytokines is implicated in disease progression.

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p38α-mediated cytokine overproduction in microglia has been linked to inflammation-induced neurotoxicity in a variety of mouse models.
“The p38α-mediated cytokine overproduction in microglia has been linked to inflammation-induced neurotoxicity in a variety of mouse models [22, 27–33].”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [27]
The Discussion reports that p38α-dependent TNFα production in mouse microglia–neuron co-cultures contributes to LPS-induced neuronal damage. The Background also mentions an earlier AD-relevant mouse model, but this paper does not itself establish the link across a variety of mouse models. (LLM, conf=0.85)
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Additional file 3 of Inflammatory, synaptic, motor, and behavioral alterations induced by gestational sepsis on the offspring at different stages of life
Granja, M. G., Alves, L. P., Leardini-Tristão, M., Saul, M. E., Bortoni, L. C., de Moraes, F. M., Ferreira, É. C., de Moraes, B. P. T., da Silva, V. Z., dos Santos, A. F. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14121412
Additional file 4 of Inflammatory, synaptic, motor, and behavioral alterations induced by gestational sepsis on the offspring at different stages of life
Granja, M. G., Alves, L. P., Leardini-Tristão, M., Saul, M. E., Bortoni, L. C., de Moraes, F. M., Ferreira, É. C., de Moraes, B. P. T., da Silva, V. Z., dos Santos, A. F. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14121415
Additional file 5 of Inflammatory, synaptic, motor, and behavioral alterations induced by gestational sepsis on the offspring at different stages of life
Granja, M. G., Alves, L. P., Leardini-Tristão, M., Saul, M. E., Bortoni, L. C., de Moraes, F. M., Ferreira, É. C., de Moraes, B. P. T., da Silva, V. Z., dos Santos, A. F. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14121418
Additional file 1 of Inflammatory, synaptic, motor, and behavioral alterations induced by gestational sepsis on the offspring at different stages of life
Granja, M. G., Alves, L. P., Leardini-Tristão, M., Saul, M. E., Bortoni, L. C., de Moraes, F. M., Ferreira, É. C., de Moraes, B. P. T., da Silva, V. Z., dos Santos, A. F. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14121406
Additional file 2 of Inflammatory, synaptic, motor, and behavioral alterations induced by gestational sepsis on the offspring at different stages of life
Granja, M. G., Alves, L. P., Leardini-Tristão, M., Saul, M. E., Bortoni, L. C., de Moraes, F. M., Ferreira, É. C., de Moraes, B. P. T., da Silva, V. Z., dos Santos, A. F. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14121409
Salvianolic acid a inhibits neuroinflammation and ameliorates Alzheimer's disease pathology via the p38 MAPK/NF-κB pathway based on network pharmacology and experimental validation
Xiao, S., Han, Y., Yan, J., Wu, L., Lin, H., Yuan, C., Song, C., & Ye, J. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.116594

Repository Citation
Xing, B., Bachstetter, A. D., Eldik, L. J. V., & Bachstetter, B. X. A. D. (2016)
Self-citation
Deficiency in p38β MAPK Fails to Inhibit Cytokine Production or Protect Neurons against Inflammatory Insult in In Vitro and In Vivo Mouse Models
Xing, B., Bachstetter, A. D., & Eldik, L. J. V. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056852 · Cited by 17 · see citing works
Self-citation
Deficiency in p38b MAPK Fails to Inhibit Cytokine Production or Protect Neurons against Inflammatory Insult in In Vitro and In Vivo Mouse Models
Xing, B., Bachstetter, A. D., & Eldik, L. J. V. (2013)
Self-citation
Gö6976 inhibits LPS-induced microglial TNFα release by suppressing p38 MAP kinase activation
Jeohn, G., Cooper, C. L., Jang, K., Liu, B., Lee, D.-S., Kim, H.-C., & Hong, J. (2002) · Neuroscience · doi:10.1016/s0306-4522(02)00356-1 · Cited by 44 · see citing works
Microglial p38α MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Aβ)
Bachstetter, A. D., Xing, B., de Almeida, L., Dimayuga, E. R., Watterson, D. M., & Van Eldik, L. J. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-79 · Cited by 282 · see citing works
Self-citation

Authors: Xing, B., Bachstetter, A. D., & Van Eldik, L. J.
Affiliations: University of Kentucky (US)
ORCID: Bachstetter, Adam D
Venue: Molecular Neurodegeneration
Publisher: Springer Science and Business Media LLC
Published: 2011-12
Volume: 6
Issue: 1
Pages: 84-84
ISSN: 1750-1326 (ISSN-L)
DOI: 10.1186/1750-1326-6-84
PMC: PMC3292986
OpenAlex: W2140508260
Cited by: 101
References: 56
Citations by year: 2026: 2 · 2025: 13 · 2024: 4 · 2023: 7 · 2022: 2 · 2021: 12 · 2020: 3 · 2019: 6 · 2018: 5 · 2017: 7 · 2016: 8 · 2015: 12 · 2014: 8 · 2013: 10 · 2012: 2
FWCI: 3.54
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: Molecular Neurodegeneration (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
UKnowledge (University of Kentucky) (submittedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders: Alzheimer's Association
Boehringer Ingelheim
National Institutes of Health
National Institute on Aging (F32AG037280)
National Institute of Neurological Disorders and Stroke (R01NS064247)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
Keywords: p38α MAPK, microglia, neuron degeneration, lipopolysaccharide, TNF-α, microglial activation, neuroinflammation, synaptic loss, neurite degeneration, conditional knockout mice, neuroprotection, central nervous system disorders
MeSH terms: Animals, Enzyme-Linked Immunosorbent Assay, Immunohistochemistry, Inflammation, Lipopolysaccharides, Nerve Degeneration, Tumor Necrosis Factor-alpha, Blotting, Western, Microglia, Mice, Knockout, Coculture Techniques, Mitogen-Activated Protein Kinase 14, Mice

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Microglial p38α MAPK is critical for LPS-induced neuron degeneration, through a mechanism involving TNFα

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