The DOI matches its Crossref record; 60 of the 61 references it cites were found in a registry or an index; none of the 5 sources its claims cite is checked for support yet.
IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline
Open accessAbstract
Significance: Dysfunction of the innate immune system is involved in the pathogenesis of Alzheimer’s disease (AD); however, the pathophysiological mechanisms underlying these dysfunctions are unclear. Here we report that stimulation of IL-33/ST2 signaling rescues memory deficits and reduces the accumulation of β-amyloid in APP/PS1 mice that exhibit select pathologies associated with AD. Although impaired IL-33/ST2 signaling is associated with early progression of AD, IL-33 injection rescues contextual memory deficits and reduces the accumulation of β-amyloid in APP/PS1 mice. IL-33 skews the microglia toward an alternative activation state with enhanced Aβ phagocytic capacity and elevated antiinflammatory gene expression, which results in a decreased proinflammatory response in the brain. Thus, this study suggests that IL-33 can be developed as a new therapeutic intervention for AD.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
IL-33 administration reversed synaptic plasticity and contextual memory deficits and reduced amyloid pathology in APP/PS1 mice by enhancing microglial Aβ phagocytosis and shifting microglia/macrophages toward an antiinflammatory phenotype. The findings support IL-33/ST2 signaling as a potential therapeutic target in Alzheimer’s disease.
Key findings
- In 6- to 7-mo-old APP/PS1 mice, i.p. IL-33 (200 ng for 2 d) dramatically reversed impaired hippocampal LTP and restored contextual fear memory at 7 d after shock.
- IL-33 reduced soluble Aβ in cortices of 10-mo-old APP/PS1 mice by 54 ± 9% (n = 3 experiments); soluble Aβx-40 and Aβx-42 decreased by ∼50% and ∼30%, respectively. It also reduced 4G8-stained amyloid plaques in 12-mo-old APP/PS1 mice, and intracerebroventricular sST2 abolished this plaque reduction.
- IL-33 increased Aβ phagocytosis: methoxy-X04-labeled Aβ was detected in ∼33% of CD11b+ myeloid cells from APP/PS1 cortices, rising to ∼47% after IL-33; Aβ uptake by resident microglia increased by ∼80%, while infiltrating monocytes remained relatively stable.
- IL-33 increased antiinflammatory Arg1 and Fizz1 mRNA in CD11b+ myeloid cells and suppressed proinflammatory IL-1β, IL-6, and NLRP3 in APP/PS1 cortices; ST2-deficient microglia abolished IL-33-stimulated Aβ uptake.
Methods
- Mouse models: APP/PS1, 5XFAD, and St2−/− mice; WT C57BL/6 controls. In vivo IL-33 was given i.p. at 200 ng per mouse for 2 consecutive days, with some experiments using intracerebroventricular sST2 via osmotic pumps.
- Outcomes included hippocampal LTP at SC-CA1 synapses, open field habituation, contextual fear conditioning, soluble/insoluble Aβ by Western blot and ELISA, 4G8 plaque immunohistochemistry, microglial Aβ phagocytosis by flow cytometry, and inflammatory gene expression by ddPCR/qRT-PCR.
- Human data: serum sST2 measured in 17 healthy controls and 18 patients with MCI (Han Chinese, age ≥60 y), with clinical diagnosis by NINCDS-ADRDA criteria.
Limitations
- The paper does not include a dedicated limitations section; it states that whether IL-33/ST2 suppression of proinflammatory gene production via MyD88 competition mediates the observed effects “awaits further study,” and that further phenotypic characterization of the microglial subset with increased Aβ phagocytic capacity is needed.
- Evident from the text: the therapeutic evidence is primarily from transgenic mouse models, and the human data are limited to cross-sectional serum sST2 in small groups (17 controls, 18 MCI), not IL-33 treatment or clinical outcomes.
- Evident from the text: long-term safety, dosing durability, and whether the murine findings extrapolate to human AD are not established.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
46 Own result · 21 Own interpretation · 3 Not checked yet · 2 Own method
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-33 injection further increased the proportion of CD11b + cells exhibiting methoxy-X04 fluorescence (∼47%; Fig. 3 F and G).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-33 administration significantly increased Aβ phagocytic uptake by resident microglia by ∼80%, whereas the percentage of Aβ-containing infiltrating monocytes remained relatively stable (Fig. 3 H and I and SI Appendix, Fig. S8 E-G).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Specifically, soluble Aβ x-40 and Aβ x-42 species, which play major synaptotoxic roles in AD (21), were decreased by ∼50% and ∼30%, respectively, in the cortices of 10-mo-old IL-33-administered APP/PS1 mice (Fig. 2B).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
plaindirectn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-33 administration reduces soluble Aβ levels and amyloid plaque deposition by promoting the recruitment and Aβ phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-33 administration increased CD68 expression in Iba1 + myeloid cells, that were in close contact with amyloid plaques (Fig. 3E).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD.”
- Also stated in: § Results · plain
“We found significantly higher levels of serum sST2, a decoy receptor of IL-33, in patients with mild cognitive impairment (MCI; with an increased risk of developing to AD in later life) compared with healthy controls (Fig. 1A);”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Results · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our 3D analysis confirmed the increased colocalization of myeloid cells and amyloid plaques in IL-33treated APP/PS1 mouse brains (Fig. 3 B and C), supporting the notion that IL-33 enhances the proximity between myeloid cells and amyloid plaques.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice.”
- Also stated in: § Results · boosted
“An i.p. injection of recombinant IL-33 (200 ng) for 2 d dramatically reversed the LTP impairment of APP/PS1 mice (Fig. 1 B and C).”
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Results · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-33 injection enhanced the recruitment of Iba1 + myeloid cells to amyloid plaques in these cortices (Fig. 3A).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice.”
- Also stated in: § Results · plain
“IL-33 treatment was able to restore the impaired freezing response of the APP/PS1 mice at 7 d after the electric shock (Fig. 1G).”
- Also stated in: § Results · boosted
“Collectively, these results demonstrate that IL-33 can rescue the synaptic dysfunction and memory deficits of APP/PS1 mice.”
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Results · plain
- The quote only partly states this claim. 3
- It may state two separate claims as one. 6
- Probably not a substantial claim. 2
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-33 rescues LTP impairment in APP/PS1 mutant mice.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-33 ameliorates memory retrieval deficits of APP/PS1 mice in fear conditioning (FC) tests.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At the concentration used (200 ng i.p. daily for 2 d), IL-33 did not affect the general health or plasma histamine level in either WT or APP/PS1 mice (SI Appendix, Fig. S4).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-33 ameliorates memory retrieval deficits of APP/PS1 mice in fear conditioning (FC) tests.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, our results demonstrate that IL-33 administration mitigates the amyloid plaque pathology in APP/PS1 mice through the enhancement of Aβ phagocytosis by resident microglia and Aβ clearance, probably by increasing neprilysin levels.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The investigators who performed the electrophysiological, immunohistochemical, RNA expression, and flow cytometry analyses and the behavioral tests were blinded to the genotypes of the mice and treatment conditions.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-33 administration ameliorates synaptic impairment and behavioral deficits in APP/PS1 mice.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data suggest that IL-33 treatment reverses contextual memory deficits in APP/PS1 mice, probably through ameliorating the hippocampal synaptic dysfunctions.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-33 administration reduces soluble Aβ levels and Aβ plaques in APP/PS1 mice.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plaindirectn = 6- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The purity of microglia/infiltrating monocyte isolation was routinely >90% as determined by fluorescence staining for CD11b and flow cytometry analysis.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Contextual Fear Conditioning.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, IL-33 treatment switches the microglia/macrophages to an alternative activation phenotype, resulting in a reduction of the proinflammatory response in the AD mouse brains.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
There is no effective therapy for AD.
“There is no effective therapy for AD, in part because of our limited knowledge of its underlying pathophysiological mechanisms.”
The paper relies on this without support.
The mechanisms underlying the onset and progression of AD remain unclear.
“The mechanisms underlying the onset and progression of AD remain unclear.”
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
“Our results support previous studies showing improved behaviour in AD mouse models associated with enhanced microglial amyloid plaque phagocytosis in response to scanning ultrasound69, and treatment with IL-33 that signals exclusively via MyD8870.”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [70]
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
“CD45 is differentially expressed on microglia (CD45lo/CD11b+) and recruited myeloid cells (CD45hi/CD11b+), and this distinction is commonly used in flow cytometry experiments to distinguish recruited myeloid cells from resident microglia in various disease states [27, 40, 41].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [27]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Furthermore, IL-33 administration ameliorated memory deficits and reduced Aβ deposition in the APP/PS1 mouse model (54).”
From The effect of Abi3 locus deletion on the progression of Alzheimer’s disease-related pathologies (2023) · cites this paper as [54]
The cited source says what the claim attributes to it.
In the citing paper
“Strikingly, activation of microglial cells by inflammatory molecules has been shown to enhance Aβ clearance by microglia [3, 26, 27].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [27]
In the citing paper
“IL-33 ameliorated AD-associated phenotypes by promoting anti-inflammatory functions, which included induction of Arg1 (80).”
From Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [80]
Citations
Cites
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984) · Neurology · doi:10.1212/wnl.34.7.939 · Cited by 27,915
Neuroinflammation in Alzheimer's disease
Heneka, M. T., Carson, M. J., Khoury, J. E., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., et al. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)70016-5 · Cited by 6,226
2016 Alzheimer's disease facts and figures
Alzheimer's Association (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.03.001 · Cited by 5,069
Schmitz, J., Owyang, A. M., Oldham, E. R., Song, Y., Murphy, E., McClanahan, T. K., Zurawski, G., Moshrefi, M., Qin, J., Li, X., et al. (2005) · Immunity · doi:10.1016/j.immuni.2005.09.015 · Cited by 3,773
Oakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1202-06.2006 · Cited by 3,530 · cited 1×
“The generation of 5XFAD mice overexpressing the K670N/M671L (Swedish), I716V (Florida), and V717I (London) mutations in human APP (695), as well as M146L and L286V mutations in human PS1, has been described previously (53).”
BackgroundNLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice
Heneka, M. T., Kummer, M. P., Stutz, A., Delekate, A., Schwartz, S., Vieira-Saecker, A., Griep, A., Axt, D., Remus, A., Tzeng, T.-C., et al. (2013) · Nature · doi:10.1038/nature11729 · Cited by 2,898
Immune attack: the role of inflammation in Alzheimer disease
Heppner, F. L., Ransohoff, R. M., & Becher, B. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3880 · Cited by 2,134
Blood-brain barrier breakdown in the aging human hippocampus
Montagne, A., Barnes, S. R., Sweeney, M. D., Halliday, M. R., Sagare, A. P., Zhao, Z., Toga, A. W., Jacobs, R. E., Liu, C. Y., Amezcua, L., et al. (2015) · Neuron · doi:10.1016/j.neuron.2014.12.032 · Cited by 2,102
Decreased Clearance of CNS β-Amyloid in Alzheimer’s Disease
Mawuenyega, K. G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J. C., Yarasheski, K. E., & Bateman, R. J. (2010) · Science · doi:10.1126/science.1197623 · Cited by 2,078
New tools for studying microglia in the mouse and human CNS
Bennett, M. L., Bennett, F. C., Liddelow, S. A., Ajami, B., Zamanian, J. L., Fernhoff, N. B., Mulinyawe, S. B., Bohlen, C. J., Adil, A., Tucker, A., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1525528113 · Cited by 1,804
Cited by
Sorted by citations
Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?
Leng, F., & Edison, P. (2021) · Nature Reviews Neurology · doi:10.1038/s41582-020-00435-y · Cited by 3,179
Interleukin-33 in health and disease
Liew, F. Y., Girard, J., & Turnquist, H. R. (2016) · Nature reviews. Immunology · doi:10.1038/nri.2016.95 · Cited by 1,178
Self-citationInterleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity
Mantovani, A., Dinarello, C. A., Molgora, M., & Garlanda, C. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.012 · Cited by 1,046
Microglia polarization from M1 to M2 in neurodegenerative diseases
Guo, S., Wang, H., & Yin, Y. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.815347 · Cited by 920
Inflammasome signalling in brain function and neurodegenerative disease
Heneka, M. T., McManus, R. M., & Latz, E. (2018) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0055-7 · Cited by 836
Vainchtein, I. D., Chin, G., Cho, F. S., Kelley, K. W., Miller, J. G., Chien, E. C., Liddelow, S. A., Nguyen, P. T., Nakao-Inoue, H., Dorman, L. C., et al. (2018) · Science · doi:10.1126/science.aal3589 · Cited by 657
Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity
Nguyen, P. T., Dorman, L. C., Pan, S., Vainchtein, I. D., Han, R. T., Nakao-Inoue, H., Taloma, S. E., Barron, J. J., Molofsky, A. B., Kheirbek, M. A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.050 · Cited by 615
“Interestingly, clearance of ECM and exogenous recombinant IL-33 are beneficial in mouse models of Alzheimer’s disease (Fu et al., 2016; Végh et al., 2014b).”
Neuroinflammation 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
“Furthermore, IL-33 injection reduced microglial reactivity, Aβ plaques, synaptic loss and cognitive deficits in a mouse model of AD 488 .”
Microglia regulation of synaptic plasticity and learning and memory
Zhou, M., Cornell, J., Salinas, S., & Huang, H.-Y. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.322423 · Cited by 548
“PTSD mice have decreased mushroom and stubby dendritic spine density in the CA1 region of the hippocampus, which is indicative of synaptic dysregulation that may lead to learning and memory impairments.”
BackgroundInfluentialInflammation: 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
Cardoso, A. L., Fernandes, A. M. A., Aguilar‐Pimentel, J. A., de Angelis, M. H., Guedes, J. R., Brito, M. A., Ortolano, S., Pani, G., Athanasopoulou, S., Gonos, E. S., et al. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.07.004 · Cited by 483
Practical considerations for choosing a mouse model of Alzheimer’s disease
Jankowsky, J. L., & Zheng, H. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0231-7 · Cited by 449
Astrocytes and microglia: In sickness and in health
Vainchtein, I. D., & Molofsky, A. V. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.01.003 · Cited by 450
Brain Pericytes As Mediators of Neuroinflammation
Rustenhoven, J., Jansson, D., Smyth, L. C., & Dragunow, M. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.12.001 · Cited by 371
Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice
Ou, Z., Kong, X., Sun, X., He, X., Zhang, L., Gong, Z., Huang, J., Xu, B., Long, D., Li, J., et al. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.12.009 · Cited by 372
Transcriptional 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
Cai, Y., Liu, J., Wang, B., Sun, M., & Yang, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.856376 · Cited by 351
Inflammation in Alzheimer’s disease: Lessons learned from microglia-depletion models
Spangenberg, E. E., & Green, K. N. (2017) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2016.07.003 · Cited by 352
Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage
Zhu, H., Wang, Z., Yu, J., Yang, X., He, F., Liu, Z., Che, F., Chen, X., Ren, H., Hong, M., et al. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2019.03.003 · Cited by 326
The IL-1β phenomena in neuroinflammatory diseases
Mendiola, A. S., & Cardona, A. E. (2017) · Journal of Neural Transmission · doi:10.1007/s00702-017-1732-9 · Cited by 328
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
Microglia in Alzheimer’s disease: pathogenesis, mechanisms, and therapeutic potentials
Miao, J., Ma, H., Yang, Y., Liao, Y., Lin, C., Zheng, J., Yu, M., & Lan, J. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1201982 · Cited by 293
Urolithin A attenuates memory impairment and neuroinflammation in APP/PS1 mice
Gong, Z., Huang, J., Xu, B., Ou, Z., Zhang, L., Lin, X., Ye, X., Kong, X., Long, D., Sun, X., et al. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1450-3 · Cited by 265
“Activated glia stimulated by Aβ has been reported to upregulate the expression of several proinflammatory chemokines and cytokines including IL-1β, IL-6, and TNF-α, which could result in an increase of Aβ production, neuronal death, and cognitive deficits [19].”
Advances in the development of new biomarkers for Alzheimer’s disease
Klyucherev, T. O., Olszewski, P., Shalimova, A. A., Chubarev, V. N., Tarasov, V. V., Attwood, M. M., Syvänen, S., & Schiöth, H. B. (2022) · Translational Neurodegeneration · doi:10.1186/s40035-022-00296-z · Cited by 241
“IL-33 is commonly associated with inflammation; however, in AD it plays a protective role through stimulation of microglia and subsequent reduction of Aβ plaques in mouse models [118].”
BackgroundBrain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia
Uemura, M. T., Maki, T., Ihara, M., Lee, V. M. ‐., & Trojanowski, J. Q. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00080 · Cited by 246
The role of the immune system in Alzheimer disease: Etiology and treatment
Jevtic, S. D., Sengar, A. S., Salter, M. W., & McLaurin, J. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.08.005 · Cited by 223
Liu, W., Taso, O., Wang, R., Bayram, S., Graham, A. C., Garcia-Reitboeck, P., Mallach, A., Andrews, W. D., Piers, T. M., Botia, J. A., et al. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa209 · Cited by 214
“ARG1-positive microglia have been shown to modify Aβ accumulation (79), and IL-33 ameliorated AD-associated phenotypes by promoting anti-inflammatory functions, which included induction of Arg1 (80).”
BackgroundDing, B., Lin, C., Liu, Q., He, Y., Ruganzu, J. B., Jin, H., Peng, X., Ji, S., Ma, Y., & Yang, W. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01981-4 · Cited by 215
“Activated microglia and astrocytes stimulated by Aβ play an important role in the release of pro-inflammatory chemokines and cytokines, which can lead to an increase in Aβ production, neuronal damage, and cognitive deficits [35].”
BackgroundWu, A., Zhou, X., Qiao, G., Yu, L., Tang, Y., Yan, L., Qiu, W., Pan, R., Yu, C., Law, B. Y. K., et al. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101202 · Cited by 196
Self-citationTREM2 dependent and independent functions of microglia in Alzheimer’s disease
Hou, J., Chen, Y., Grajales-Reyes, G., & Colonna, M. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00588-y · Cited by 191
Liu, Y., Shen, X. P., Zhang, Y., Zheng, X., Cepeda, C., Wang, Y., Duan, S., & Tong, X. (2023) · Glia · doi:10.1002/glia.24343 · Cited by 199
“However, the activation of microglia, either by LPS injections or in other neurodevelopmental and psychiatric disorders, causes exacerbated synaptic activities, leading to deficits in learning and cognition in AD (Fu et al., 2016; Kim et al., 2017; Li et al., 2021; Zuckerman et al., 2018).”
BackgroundExploiting 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
“IL-33 levels are low in the brains of AD patients, and serum levels of soluble ST2, the IL-33 receptor, are high in the brains of patients with mild cognitive impairment [179, 180].”
BackgroundYe, X., Zhu, M., Che, X., Wang, H., Liang, X., Wu, C., Xue, X., & Yang, J. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1644-8 · Cited by 189
Targeting neuroinflammation in Alzheimer’s disease: from mechanisms to clinical applications
Si, Z.-Z., Zou, C.-J., Mei, X., Mei, X., Luo, H., Shen, Y., Hu, J., Li, X.-X., Wu, L., & Liu, Y. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.353484 · Cited by 196
“Cytokines and Immune Signaling in Alzheimer’s Disease Over the years, many natural immune cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-10, IL-12, IL-18, IL-23, IL-33, IL-34, IL-1β, and type I interferon, have been suggested to be tightly related to diverse AD processes (Mizuno et al., 2011; Bha…”
BackgroundXu, J., Chen, Z., Yu, F., Liu, H., Ma, C., Xie, D., Hu, X., Leak, R. K., Chou, S. H. Y., Stetler, R. A., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2018497117 · Cited by 180
“IL-33 also enhances microglial clearance of β-amyloid by activating the ST2/p38 signaling, reducing cerebral inflammation and rescuing memory deficits in Alzheimer’s disease models (38).”
BackgroundRider, P., Voronov, E., Dinarello, C. A., Apte, R. N., & Cohen, I. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1601342 · Cited by 185
“Although the reports of novel alarmins or stressorins and their function in immune activation are rapidly on the rise, uncovering the full potential of their inhibition as a new therapeutic approach will require extensive study of the intracellular pathways leading to their release and inactivation under different phy…”
BackgroundOzone exposure induces respiratory barrier biphasic injury and inflammation controlled by IL-33
Michaudel, C., Mackowiak, C., Maillet, I., Fauconnier, L., Akdiş, C. A., Sokołowska, M., Dreher, A., Tan, H. T., Quesniaux, V. F. J., Ryffel, B., et al. (2018) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2017.11.044 · Cited by 172
Neuroinflammation, gut microbiome, and Alzheimer's disease
Lin, L., Zheng, L. J., & Zhang, L. J. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-0983-2 · Cited by 147
Italiani, P., Puxeddu, I., Napoletano, S., Scala, E., Melillo, D., Manocchio, S., Angiolillo, A., Migliorini, P., Boraschi, D., Vitale, E., et al. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1376-1 · Cited by 154
Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in the adult hippocampus
Wang, Y., Fu, W., Cheung, K., Hung, K.-W., Chen, C., Geng, H.-Y., Yung, W., Qu, J. Y., Fu, A. K. Y., & Ip, N. Y. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2020810118 · Cited by 139
“It has been reported that Alzheimer’s disease patients also exhibited decreased IL-33 transcript levels in the brain and impaired IL-33/ST2 signaling (37, 80).”
BackgroundResultSelf-citationFu, W., Wang, X., & Ip, N. Y. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00402 · Cited by 137
Self-citationThe IL-1 family cytokines and receptors in autoimmune diseases
Migliorini, P., Italiani, P., Pratesi, F., Puxeddu, I., & Boraschi, D. (2020) · Autoimmunity Reviews · doi:10.1016/j.autrev.2020.102617 · Cited by 137
The immune system and psychiatric disease: a basic science perspective
Bennett, F. C., & Molofsky, A. V. (2019) · Clinical & Experimental Immunology · doi:10.1111/cei.13334 · Cited by 141
Piirainen, S., Youssef, A. M., Song, C., Kalueff, A. V., Landreth, G. E., Malm, T., & Tian, L. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.01.046 · Cited by 129
IL-33 exacerbates liver sterile inflammation by amplifying neutrophil extracellular trap formation
Yazdani, H. O., Chen, H., Tohme, S. T., Tai, S., van der Windt, D. J., Loughran, P., Rosborough, B. R., Sud, V., Beer–Stolz, D., Turnquist, H. R., et al. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.09.010 · Cited by 131
Long, Y., Li, X., Deng, J., Ye, Q., Li, D., Ma, Y., Wu, Y., Hu, Y., He, X.-F., Wen, J., et al. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102160 · Cited by 130
Boza‐Serrano, A., Yang, Y., Paulus, A., & Deierborg, T. (2018) · Scientific Reports · doi:10.1038/s41598-018-19699-y · Cited by 131
“For instance, p38 MAPK protein has been linked with microglial response by directly promoting the expression of inflammatory cytokine such as TNF-α, IL6 or IL-1β via TLR’s ligands or in the presence of Aβ37.”
IL-1 family cytokines in inflammation and immunity
Garlanda, C., Ceglie, I. D., & Jaillon, S. (2025) · Cellular and Molecular Immunology · doi:10.1038/s41423-025-01358-8 · Cited by 153
“In AD animal models, IL-33 expression has been associated with reduced disease pathology, whereas increased IL-33 plasma levels have been observed in patients treated with the neuroprotective compound homotaurine [247, 248].”
IL-33 improves wound healing through enhanced M2 macrophage polarization in diabetic mice
He, R., Yin, H., Yuan, B., Liu, T., Luo, L., Huang, P., Dai, L., & Zeng, K. (2017) · Molecular Immunology · doi:10.1016/j.molimm.2017.06.249 · Cited by 121
“…variety of studies that IL-33, known as an inducer of Th2type immune response, exhibits a central role in the treatment of situations such as stroke, transplantation, experimental autoimmune uveitis and Alzheimer's disease (Luo et al., 2015; Yin et al., 2010; Barbour et al., 2014; Fu et al., 2016).”
BackgroundSynaptic Elimination in Neurological Disorders
Cardozo, P. L., de Lima, I. B. Q., Maciel, E. M. A., Silva, N. C., Dobránsky, T., & Ribeiro, F. M. (2019) · Current Neuropharmacology · doi:10.2174/1570159x17666190603170511 · Cited by 115
The role of innate immunity in Alzheimer's disease
Ennerfelt, H. E., & Lukens, J. R. (2020) · Immunological Reviews · doi:10.1111/imr.12896 · Cited by 124
Male-specific IL-33 expression regulates sex-dimorphic EAE susceptibility
Russi, A. E., Ebel, M. E., Yang, Y., & Brown, M. A. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1710401115 · Cited by 117
Lau, S.-F., Chen, C., Fu, W.-Y., Qu, J. Y., Cheung, T. H., Fu, A. K. Y., & Ip, N. Y. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107530 · Cited by 114
“IL-33 Enhances the Chemotactic Response of a Microglial Subpopulation toward AbPlaques in APP/PS1 Mice IL-33 injection enhances the co-localization of microglia with Ab plaques and promotes Ab clearance (Fu et al., 2016).”
BackgroundInfluentialSelf-citationPharmacological approaches to mitigate neuroinflammation in Alzheimer’s disease
Uddin, M. S., Kabir, M. T., Mamun, A. A., Barreto, G. E., Rashid, M., Perveen, A., & Ashraf, G. M. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106479 · Cited by 121
Ruganzu, J. B., Zheng, Q., Wu, X., He, Y., Peng, X., Jin, H., Zhou, J., Ma, R., Ji, S., Ma, Y., et al. (2020) · Experimental Neurology · doi:10.1016/j.expneurol.2020.113506 · Cited by 117
Kempuraj, D., Selvakumar, G. P., Thangavel, R., Ahmed, M. E., Zaheer, S. A., Raikwar, S. P., Iyer, S. S., Bhagavan, S., Ramaswamy, S. B., & Zaheer, A. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00703 · Cited by 108
“However, another study showed that injection of IL33 led to improved memory deficit in APP/PS1 AD mice model (Fu et al., 2016).”
BackgroundDarwish, S. F., Elbadry, A. M. M., Elbokhomy, A. S., Salama, G. A., & Salama, R. M. (2023) · Frontiers in Aging · doi:10.3389/fragi.2023.1231706 · Cited by 110
“Alzheimer’s disease is the prevailing type of dementia, associated with damaged locomotor ability, thinking, judgment ability, increasing memory loss, and cognitive decline (Fu et al., 2016).”
BackgroundFairlie‐Clarke, K. J., Barbour, M., Wilson, C., Hridi, S. U., Allan, D., & Jiang, H. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02596 · Cited by 101
“Patients with mild cognitive impairment, who have an increased risk of AD development, also exhibit a significantly higher serum level of sST2 (52).”
BackgroundKong, F., Jiang, X., Wang, R., Zhai, S., Zhang, Y., & Wang, D. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01967-2 · Cited by 99
“Aβ can activate neuroglia and stimulate the expression of pro-inflammatory chemokines such as TNF-α and ILs, perhaps leading to increased Aβ production and neuronal death [36, 37].”
BackgroundAutoimmune Neuroinflammatory Diseases: Role of Interleukins
Khan, A. W., Farooq, M., Hwang, M.-J., Haseeb, M., & Choi, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24097960 · Cited by 107
Mitochondrial dysfunction in chronic neuroinflammatory diseases (Review)
Qin, P., Sun, Y., & Li, L. (2024) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2024.5371 · Cited by 106
“Excessive activation of microglial cells and reduced phagocytic ability leads to increased accumula‑ tion of A β plaques and τ hyperphosphorylation, exacerbating neuroinflammation (164).”
BackgroundZhao, X., Li, S., Gaur, U., & Zheng, W. (2020) · Aging and Disease · doi:10.14336/ad.2019.0813 · Cited by 91
“AD is one of the neurodegenerative disorders that affects older population and is clinically characterized by progressive loss of memory along with decline in multiple cognitive abilities [42, 43].”
BackgroundScholtzova, H., Do, E., Dhakal, S., Sun, Y., Liu, S., Mehta, P. D., & Wisniewski, T. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.1967-16.2016 · Cited by 82
“Similarly, APP/PS1 mice treatment with IL33, which skews microglia toward an alternative activation state with enhanced phagocytic capacity, resulted in AD pathology amelioration in association with Iba1 microglia in the vicinity of amyloid deposits (Fu et al., 2016).”
BackgroundWu, P.-J., Hung, Y.-F., Liu, H., & Hsueh, Y. (2017) · NeuroImmunoModulation · doi:10.1159/000477092 · Cited by 85
Cao, K., Liao, X., Lü, J., Yao, S., Wu, F., Zhu, X., Shi, D., Wen, S., Liu, L., & Zhou, H. Y. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1169-6 · Cited by 84
“have shown that IL-33 ameliorated cognitive decline in an animal model of Alzheimer’s disease [38].”
Tzeng, T.-T., Chen, C.-C., Chen, C., Tsay, H.-J., Lee, L., Chen, W.-P., Shen, C.-C., & Shiao, Y. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19020598 · Cited by 86
Early Life Stress and Epigenetics in Late-onset Alzheimer’s Dementia: A Systematic Review
Lemche, E. (2018) · Current Genomics · doi:10.2174/1389202919666171229145156 · Cited by 84
Shen, Z., Bao, X., & Wang, R. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00314 · Cited by 77
Benítez, D. P., Jiang, S., Wood, J. I., Wang, R., Hall, C. M., Peerboom, C., Wong, N. S. M., Stringer, K. M., Vitanova, K. S., Smith, V. C., et al. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00457-0 · Cited by 81
“Extending that role into a transgenic mouse model of Alzheimer’s disease, IL33 shifted the activation state of microglia from a proinflammatory profile towards a profile expressing anti-inflammatory genes with improved phagocytosis and again improved fearconditioned learning [64].”
BackgroundLiu, R., Yang, J., Liu, L., Lü, Z., Shi, Z., Ji, W., Shen, J., & Zhang, X. (2019) · Advanced Science · doi:10.1002/advs.201901555 · Cited by 79
Microglia and Wnt Pathways: Prospects for Inflammation in Alzheimer’s Disease
Yang, Y., & Zhang, Z. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00110 · Cited by 76
He, Z., Yang, Y., Xing, Z., Zuo, Z., Wang, R., Gu, H., Qi, F., & Yao, Z. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2644-4 · Cited by 79
Rivera-Escalera, F., Pinney, J. J., Owlett, L., Ahmed, H., Thakar, J., Olschowka, J. A., Elliott, M. R., & O’Banion, M. K. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1645-7 · Cited by 75
IL-33 and its decoy sST2 in patients with Alzheimer’s disease and mild cognitive impairment
Saresella, M., Marventano, I., Piancone, F., La Rosa, F., Galimberti, D., Fenoglio, C., Scarpini, E., & Clerici, M. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01806-4 · Cited by 75
Xiong, R., Zhou, X., Tang, Y., Wu, J., Sun, Y., Teng, J., Pan, R., Law, B. Y. K., Zhao, Y., Qiu, W., et al. (2020) · Phytotherapy Research · doi:10.1002/ptr.6849 · Cited by 78
“The expression of ZO-1 and Claudin 5 in endothelial cells of tissue was detected by immunohistochemical method as previously described (Fu et al., 2016).”
MethodSelf-citationMacrophages originated IL-33/ST2 inhibits ferroptosis in endometriosis via the ATF3/SLC7A11 axis
Wu, Q., Liang, Z., Jiang, J., Feng, X., Liu, J., Zhang, Z., Wang, H., Wang, N., Gou, Y., Li, Z., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06182-4 · Cited by 81
“It is also worth mentioning that IL-33 induces macrophage anti-in fl ammatory polarization and stimulates the formation of splenic red pulp macrophages (RPMs) that regulate erythrocyte homeostasis and support iron recycling [9, 10].”
Cortese, G. P., & Bürger, C. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.08.027 · Cited by 77
AmeliMojarad, M., & AmeliMojarad, M. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14856 · Cited by 73
Wang, Y., Fu, A. K. Y., & Ip, N. Y. (2021) · FEBS Journal · doi:10.1111/febs.15878 · Cited by 75
Self-citationShe, L., Sun, J., Li, X., Li, A., Li, L., Wu, H., Ren, J., Wang, W., Liang, G., & Zhao, X. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.155168 · Cited by 81
Roles of Cytokines in Alzheimer’s Disease
Chen, Z., Balachandran, Y. L., Chong, W. P., & Chan, K. W. Y. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25115803 · Cited by 73
“Microglia are professional phagocytes and play a critical role in A β plaque clearance in the AD brain [3].”
BackgroundInfluentialNeurovascular unit, neuroinflammation and neurodegeneration markers in brain disorders
Kempuraj, D., Dourvetakis, K. D., Cohen, J., Valladares, D. S., Joshi, R. S., Kothuru, S. P., Anderson, T., Chinnappan, B., Cheema, A. K., Klimas, N. G., et al. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1491952 · Cited by 78
Noh, M., Kwon, H. S., Kwon, M., Nahm, M., Jin, H. K., Bae, J., & Kim, S. H. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00867-4 · Cited by 94
“Interleukin (IL) − 33, a cytokine belonging to the IL-1 family, also promotes microglial recruitment and Aβ clearance through the ST2/p38 signaling pathway, leading to a reduction in soluble Aβ and amyloid plaque burden [124].”
The VCAM1–ApoE pathway directs microglial chemotaxis and alleviates Alzheimer’s disease pathology
Lau, S.-F., Wu, W., Wong, H. Y., Ouyang, L., Qiao, Y., Xu, J., Lau, J. H.-Y., Wong, C., Jiang, Y., Holtzman, D. M., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00491-1 · Cited by 70
Self-citationThe Role of Vascular Cells in Pancreatic Beta-Cell Function
Burganova, G., Bridges, C. A., Thorn, P., & Landsman, L. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.667170 · Cited by 70
Zhang, S. R., Piepke, M., Chu, H. X., Broughton, B. R. S., Shim, R., Wong, C. H. Y., Lee, S., Evans, M. A., Vinh, A., Sakkal, S., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.121560 · Cited by 67
Xie, D., Liu, H., Xu, F., Su, W., Ye, Q., Yu, F., Austin, T. J., Chen, J., & Hu, X. (2021) · Stroke · doi:10.1161/strokeaha.120.032444 · Cited by 65
Duan, Y., Tao, Y., Qu, Z., Chen, Y., Miranda, A., Zhou, X., Lok, K.-C., Chen, Y., Fu, A. K. Y., Gradinaru, V., et al. (2021) · Nature Biomedical Engineering · doi:10.1038/s41551-021-00759-0 · Cited by 64
Self-citationType 2 immunity in the brain and brain borders
Mamuladze, T., & Kipnis, J. (2023) · Cellular and Molecular Immunology · doi:10.1038/s41423-023-01043-8 · Cited by 67
Chen, C., Liang, Z., Zhou, B., Li, X., Lui, C., Ip, N. Y., & Qu, J. Y. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00306 · Cited by 63
Self-citationDual roles of interleukin-33 in cognitive function by regulating central nervous system inflammation
Rao, X., Hua, F., Zhang, L., Lin, Y., Fang, P., Chen, S., Ying, J., & Wang, X. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03570-w · Cited by 64
“IL-33 treatment significantly reversed the LTP impairment and contextual memory deficits of APP/PS1 mice, while also improving habituation to a new environment, which confirmed that IL-33 treatment reversed the reduction of synaptic plasticity in the hippocampus and cognitive deficits in APP/PS1 mice [2, 24].”
BackgroundInfluentialInterleukin‐33 regulates tissue remodelling and inhibits angiogenesis in the eye
Theodoropoulou, S., Copland, D. A., Liu, J., Wu, J., Gardner, P. J., Ozaki, E., Doyle, S., Campbell, M. D., & Dick, A. D. (2016) · The Journal of Pathology · doi:10.1002/path.4816 · Cited by 62
“IL-33 prevents cognitive decline in mouse models of Alzheimer’s disease [47] and inhibits atherosclerosis [45], and here IL-33 also directly inhibited choroidal fibroblast activity, implicating a potentially wider role clinically.”
BackgroundImpact of aging immune system on neurodegeneration and potential immunotherapies
Liang, Z., Zhao, Y., Ruan, L., Zhu, L., Jin, K., Zhuge, Q., Su, D., & Zhao, Y. L. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.07.006 · Cited by 64
“However, it was recently reported that serum levels of soluble ST2, a decoy receptor for IL-33, significantly increased in patients with mild cognitive impairment, indicating that impaired IL-33/ST2 signaling pathwaymaycontribute to the pathogenesis of AD in APP/PS1mice (Fu et al., 2016).”
Targeting IL-33/ST2 signaling: regulation of immune function and analgesia
Fattori, V., Hohmann, M. S., Rossaneis, A. C., Manchope, M. F., Alves-Filho, J. C., Cunha, T. M., Cunha, F. Q., & Verri, W. A., Jr. (2017) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2017.1398734 · Cited by 60
“In fact, immunohistochemical analysis of spinal cord tissue after SCI demonstrated that rIL-33 treatment decreases the activation of astrocytes but does not alter microglial activity in vivo [33], despite evidence indicating that microglia express ST2 given IL-33 induce M2 polarization or activation of microglia in vi…”
Targeting the IL33–NLRP3 axis improves therapy for experimental cerebral malaria
Strangward, P., Haley, M., Albornoz, M. G., Barrington, J., Shaw, T. N., Dookie, R. S., Zeef, L. A. H., Baker, S. M., Winter, E., Tzeng, T.-C. J., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1801737115 · Cited by 60
“(A) Peripheral parasitemia, (B) survival curves, and (C) RMCBS scores of mice after infection (d0) and drug treatment (gray box).”
BackgroundMethodResultInfluentialSelf-citationChandra, S., Di Meco, A., Dodiya, H. B., Popovic, J., Cuddy, L. K., Weigle, I. Q., Zhang, X., Sadleir, K., Sisodia, S. S., & Vassar, R. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00635-2 · Cited by 58
Mechanisms of microglia-mediated synapse turnover and synaptogenesis
Ball, J. B., Green‐Fulgham, S. M., & Watkins, L. R. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102336 · Cited by 64
Carlock, C., Wu, J., Shim, J., Moreno‐González, I., Pitcher, M. R., Hicks, J., Suzuki, A., Iwata, J., Quevado, J., & Lou, Y. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.142 · Cited by 61
The Role of Glial Cells in Synaptic Dysfunction: Insights into Alzheimer's Disease Mechanisms
Yu, Y., Chen, R., Mao, K., Deng, M., & Li, Z. (2023) · Aging and Disease · doi:10.14336/ad.2023.0718 · Cited by 62
“IL-33 also triggered a transition in microglia status and increased phagocytosis of Aβ plaques in APP/PS1 mice [91, 92].”
BackgroundInflammasomes and Cell Death: Common Pathways in Microparticle Diseases
Rashidi, M., Wicks, I. P., & Vince, J. E. (2020) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2020.06.005 · Cited by 57
Metadata
- Authors
- Fu, A. K. Y., Hung, K.-W., Yuen, M. Y. F., Zhou, X., Mak, D. S. Y., Chan, I. C. W., Cheung, T. H., Zhang, B., Fu, W.-Y., Liew, F. Y., & Ip, N. Y.
- Affiliations
- Hong Kong University of Science and Technology (HK)
- Second Affiliated Hospital of Zhejiang University (CN)
- Soochow University (CN)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-04-18
- Volume
- 113
- Issue
- 19
- Pages
- E2705-13
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4868478
- OpenAlex
- W2342031861
- Semantic Scholar
- 1eac3f908af98105c0179fde2edb52b24e9f5d0c
- Cited by
- 369
- References
- 61
- Citations by year
- 2026: 18 · 2025: 41 · 2024: 45 · 2023: 39 · 2022: 33 · 2021: 48 · 2020: 40 · 2019: 24 · 2018: 35 · 2017: 31 · 2016: 14
- FWCI
- 27.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Keywords
- IL-33, Alzheimer's disease, soluble ST2, amyloid-beta, microglial activation, innate immunity, synaptic plasticity, memory impairment, APP/PS1 mice, amyloid plaques, p38 MAPK signaling, microglial polarization, neuroinflammation, NLRP3 inflammasome, IL-1β, interleukin-6
- MeSH terms
- Interleukin-33, Alzheimer Disease, Animals, Brain, Cognition Disorders, Female, Male, Mice, Transgenic, Cytokines, Treatment Outcome, Neuroprotective Agents, 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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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
