Toll-like receptor 2 confers partial neuroprotection during prion disease
Open accessAbstract
Neuroinflammation and neurodegeneration are common during prion infection, but the mechanisms that underlie these pathological features are not well understood. Several components of innate immunity, such as Toll-like receptor (TLR) 4 and Complement C1q, have been shown to influence prion disease. To identify additional components of innate immunity that might impact prion disease within the central nervous system (CNS), we screened RNA from brains of pre-clinical and clinical 22L-infected mice for alterations in genes associated with innate immunity. Transcription of several genes encoding damage-associated molecular pattern (DAMP) proteins and receptors were increased in the brains of prion-infected mice. To investigate the role of some of these proteins in prion disease of the CNS, we infected mice deficient in DAMP receptor genes Tlr2, C3ar1, and C5ar1 with 22L scrapie. Elimination of TLR2 accelerated disease by a median of 10 days, while lack of C3aR1 or C5aR1 had no effect on disease tempo. Histopathologically, all knockout mouse strains tested were similar to infected control mice in gliosis, vacuolation, and PrPSc deposition. Analysis of proinflammatory markers in the brains of infected knockout mice indicated only a few alterations in gene expression suggesting that C5aR1 and TLR2 signaling did not act synergistically in the brains of prion-infected mice. These results indicate that signaling through TLR2 confers partial neuroprotection during prion infection.
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Depletion of DAMP receptor genes Tlr2, C3ar1, and C5ar1 in a prion mouse model only leads to slightly increased survival in the Tlr2 model, while C3ar1 and C5ar1 do not influence prion disease course.
“Interestingly, depletion of any of the DAMP receptor genes Tlr2, C3ar1, and C5ar1 in a prion mouse model only led to a slightly increased survival in the Tlr2-model, while C3ar1, and C5ar1 did not influence prion disease course [82].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [82]
Transcription of several genes encoding DAMP proteins and receptors such as Toll-like receptors or proteins of the complement cascade is increased in the brains of prion-infected mice.
“In addition to the upregulation of PAMPs in prion diseases, the transcription of several genes encoding damage-associated molecular pattern (DAMP) proteins and receptors such as Toll-like receptors or proteins of the complement cascade are also increased in the brains of prion-infected mice [70,82].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [82]
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“Moreover, mice lacking TLR2 (C57BL/6, infected with 22L) or TLR4 (C3H/HeJ, infected with 139A or Me7) showed significant acceleration of prion progression, suggesting a protective function of TLR signaling in prion disease [87,88].”
BackgroundType-I Interferons in Alzheimer's Disease and Other Tauopathies
Sanford, S., & McEwan, W. A. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.949340 · Cited by 41 · see citing works
Shinjyo, N., Kagaya, W., & Pekna, M. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.710390 · Cited by 32 · see citing works
Microbial amyloids in neurodegenerative amyloid diseases
Sampson, T. R. (2023) · FEBS Journal · doi:10.1111/febs.17023 · Cited by 25 · see citing works
Toll-like receptor 2 (TLR2)-deficiency impairs male mouse recovery from a depression-like state
Medina-Rodriguez, E. M., Cheng, Y., Michalek, S. M., Beurel, E., & Jope, R. S. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.05.068 · Cited by 18 · see citing works
“, 2007), prion disease (Carroll et al., 2018), and cognitive decline in mouse Alzheimer’s disease models (Pourbadie et al.”
BackgroundIntranasally delivered mesenchymal stromal cells decrease glial inflammation early in prion disease
Hay, A. J. D., Latham, A. S., Mumford, G., Hines, A. D., Risen, S. J., Gordon, E., Siebenaler, C., Gilberto, V. S., Zabel, M. D., & Moreno, J. A. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1158408 · Cited by 17 · see citing works
“1% Rocky Mountain Laboratories (RML) strain mouse-adapted scrapie brain homogenate elicits a similar upregulation of genes for anti-inflammatory molecules and growth factors, suggesting that AdMSCs respond to factors in the prion-infected brain, such as damage-associated molecular patterns (DAMPs) and the cytokine mil…”
BackgroundLoss of Homeostatic Microglia Signature in Prion Diseases
Wang, Y., Hartmann, K., Thies, E., Mohammadi, B., Altmeppen, H., Sepulveda-Falla, D., Glatzel, M., & Krasemann, S. (2022) · Cells · doi:10.3390/cells11192948 · Cited by 12 · see citing works
“In addition to the upregulation of PAMPs in prion diseases, the transcription of several genes encoding damage-associated molecular pattern (DAMP) proteins and receptors such as Toll-like receptors or proteins of the complement cascade are also increased in the brains of prion-infected mice [70,82].”
BackgroundLiu, C., Cai, Y., Ma, Q., & Sun, W. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1731995 · Cited by 13 · see citing works
“Complement fragments C3a, C5a, and C5b bind membrane receptors and initiate multifaceted pro-in fl ammatory signaling (23).”
Makarava, N., Safadi, T., Bocharova, O. V., Mychko, O., Pandit, N. P., Molesworth, K., Eyo, U. B., & Baskakov, I. V. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03542-z · Cited by 13 · see citing works
“These findings are in agreement with previous bulk transcriptomic studies reporting stable or even increased P2ry12 mRNA levels in brains of RML-, 22L-, and ME7-infected mice [46, 50, 51].”
Hay, A. J. D., Popichak, K. A., Mumford, G., Shirley, P. M., Bian, J., Wolfrath, L., Lei, S., Eggers, M., Nicholson, E. M., Tjalkens, R. B., et al. (2025) · PLoS Pathogens · doi:10.1371/journal.ppat.1012582 · Cited by 10 · see citing works
Autophagy and Cell Death in Alzheimer’s, Parkinson’s and Prion Diseases
Ribarič, S., & Ribarič, I. M. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.86706 · Cited by 8 · see citing works
“[216] Carroll JA, Race B, Williams K, Chesebro B.”
BackgroundA new hope: Mitochondria, a critical factor in the war against prions
Zambrano, K., Barba, D., Castillo, K., Robayo, P., Arizaga, E., Caicedo, A., & Gavilanes, A. W. D. (2022) · Mitochondrion · doi:10.1016/j.mito.2022.05.004 · Cited by 8 · see citing works
Innate Immune Mechanisms in the Central Nervous System
Shastri, A., Yasmin, H., & Kishore, U. (2025) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-85340-1_15 · Cited by 4 · see citing works
García-Martínez, M., Cortez, L. M., Otero, A., Betancor, M., Serrano, B., Bolea, R., Badiola, J. J., & Garza, M. C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073579 · Cited by 4 · see citing works
“Our findings highlight TLR2 downregulation as a potential target for such an approach, as this may induce a shift in microglia from a neurotoxic to a neuroprotective phenotype [63].”
BackgroundResultInfluentialVerma, R., Kailashiya, J., Mukherjee, A., Chaurasia, R. N., & Dash, D. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1534235 · Cited by 2 · see citing works
“Prion has also been shown to promote the transcription of DAMP receptors in neuronal cells (Carroll et al., 2018) and activate NLRP3 in fl ammasome in microglial cells (Shi et al., 2012).”
da Silva, D. G., de Carvalho, I. L. Q., Toscano, E. C. D. B., Santos, B. S. Á. D. S., Oliveira, B. D. S., Campos, M. A., da Fonseca, F. G., Camargos, Q. M., de SOUSA, G. F., Caliari, M. V., et al. (2020) · Journal of Veterinary Medical Science · doi:10.1292/jvms.20-0204 · Cited by 1 · see citing works
“Activated microglia induced by expression of Toll-like receptors (TLRs) promotes secretion of type I interferons [13, 52], leading to neuroinflammatory response [12, 26, 30].”
BackgroundHay, A. J. D., Popichak, K. A., Zabel, M. D., & Moreno, J. A. (2023) · Journal of Visualized Experiments · doi:10.3791/65565 · Cited by 1 · see citing works
Expression of Toll-like receptors in the cerebellum during pathogenesis of prion disease
Liao, X., Zhu, W., Liao, X., Liu, W., Hou, Y., & Wan, J. (2024) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2024.1341901 · Cited by 1 · see citing works
Loss of region-specific glial homeostatic signature in prion diseasesPreprint
Makarava, N., Chang, J. C., Molesworth, K., & Baskakov, I. V. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.21203/rs.2.17016/v1 · Cited by 1 · see citing works
- Authors
- Carroll, J. A., Race, B., Williams, K., & Chesebro, B.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Carroll, James A.
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2018-12-31
- Volume
- 13
- Issue
- 12
- Pages
- e0208559
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC6312208
- OpenAlex
- W2906803945
- Cited by
- 22
- References
- 84
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 3 · 2020: 3 · 2019: 3
- FWCI
- 0.80
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- creativecommons.org/publicdomain/zero/1.0/ (vor)
- Locations
- PLoS ONE (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institute of Allergy and Infectious Diseases (1ZIAAI000937-14)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- TLR2, prion disease, scrapie, neuroprotection, innate immunity, damage-associated molecular patterns, C3AR1, C5aR1, neuroinflammation, neurodegeneration, knockout mice, pro-inflammatory gene expression, prion protein deposition
- MeSH terms
- Neuroprotection, Anaphylatoxins, Animals, Brain, Complement System Proteins, Disease Susceptibility, Immunity, Innate, Mice, Inbred C57BL, Receptors, Complement, RNA, Severity of Illness Index, Signal Transduction, Gene Expression, Cytokines, Prion Diseases, Mice, Knockout, Chemokines, Receptor, Anaphylatoxin C5a, Toll-Like Receptor 2, Mice
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