MicroRNA 146a (miR-146a) Is Over-Expressed during Prion Disease and Modulates the Innate Immune Response and the Microglial Activation State

In the paper

“Some evidence also exists suggesting that this response is independent of phagocytic clearance pathways that appear to be MyD88 dependent [53].”

What the sources say

• Disputed

  The section on GBS internalization says MyD88 expression had no effect on macrophages’ ability to take up GBS. The section on toxic oxygen species distinguishes CR3-mediated phagocytosis from MyD88-dependent bactericidal activity as independent processes. Thus, the paper supports their independence but says the opposite of the claim’s characterization of phagocytic clearance as MyD88 dependent. (LLM, conf=0.89)

  Checked by a reasoning model — may be wrong.

  cites [53] P Henneke, 2002, Cellular activation, phagocytosis, and bactericidal activity against group B streptococcus involve parallel myeloid differentiation factor 88-dependent and independent signaling pathways., J Immunol sourceExperimental — accuracy not yet measured

In the paper

“The neuronal cluster included miR-124, a miRNA that is especially abundant in neurons affirming the specificity of the methodology [20]–[22].”

What the sources say

• Partly supported

  The passage labeled Abstract (no page given) reports that miR-124 variants accounted for 25%–48% of miRNAs in mouse cortex, cerebellum, and midbrain, supporting abundance in brain tissue. It does not establish that miR-124 is especially abundant specifically in neurons rather than other brain cells. The neuronal cluster and what it affirms about the citing study’s methodology are the citing authors’ interpretation, not findings of this source. (LLM, conf=0.85)

  cites [20] M Lagos-Quintana, 2002, Identification of tissue-specific microRNAs from mouse., Curr Biol sourceExperimental — accuracy not yet measured
• Partly supported

  In “Diverse miRNA expression patterns in mammalian organs” (page not supplied), the paper places miR-124a and miR-124b in a brain-expressed cluster. In “A subset of brain-expressed miRNAs is induced in retinoic acid-treated EC cells” (page not supplied), it reports their induction during neuronal differentiation, but says it did not examine expression in glial cells. It therefore supports the cluster finding, not the stronger assertion that miR-124 is especially abundant in neurons specifically. (LLM, conf=0.86)

  cites [21] LF Sempere, 2004, Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation., Genome Biol sourceExperimental — accuracy not yet measured
• Supported

  The Discussion states that miR-124a is expressed preferentially in embryonic neurons, supporting the neuron-enrichment point attributed to this source. The neuronal cluster and the conclusion about methodology are the citing authors’ own observations, not findings this citation needs to establish. (LLM, conf=0.90)

  cites [22] AM Krichevsky, 2006, Specific microRNAs modulate embryonic stem cell-derived neurogenesis., Stem Cells source

In the paper

“The microglial cell-line enriched cluster contained 20 miRNAs including miR-146a and a number of other miRNAs reportedly involved in inflammation, such as miR-155, miR-221 [23] and miR-147, a microRNA that is induced upon Toll-like receptor (TLR) stimulation and regulates murine macrophage inflammatory responses [24].”

What the sources say

• Supported

  The Results report that miR-147 was induced in macrophages stimulated through TLR2, TLR3, and TLR4 and that miR-147 mimics reduced inflammatory cytokine production. The Discussion likewise describes miR-147 as part of a negative-feedback loop regulating murine macrophage inflammatory responses. (LLM, conf=0.95)

  cites [24] G Liu, 2009, miR-147, a microRNA that is induced upon toll-like receptor stimulation, regulates murine macrophage inflammatory responses., Proc Natl Acad Sci U S A source

In the paper

“MiR-146a is reported to be up-regulated in LPS stimulated human macrophages, however, the microglial surface receptor that is engaged leading to activation during prion pathogenesis is unknown [16].”

What the sources say

• Partly supported

  The Results (page not provided) report that miR-146a was strongly induced after LPS treatment in human THP-1 and HL-60 myeloid cell lines. The paper identifies THP-1 as a monocytic leukemia cell line; it does not establish the finding in human macrophages. (LLM, conf=0.88)

  cites [16] KD Taganov, 2006, NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses., Proc Natl Acad Sci U S A sourceExperimental — accuracy not yet measured

In the paper

“CFH has also been reported to be a direct target of miR-146a and potentially important in inflammation in Alzheimer's disease [32], [33].”

What the sources say

• ?Not checked — no full text of the sourcecites [32] AI Pogue, 2009, Characterization of an NF-kappaB-regulated, miRNA-146a-mediated down-regulation of complement factor H (CFH) in metal-sulfate-stressed human brain cells., J Inorg Biochem source
• Supported

  The supplied passage labeled Abstract (passages 1–2; no page supplied) reports that miRNA-146a base-pairs with the CFH mRNA 3′-UTR and down-regulates CFH. It also proposes a link between miRNA-146a signaling and inflammatory responses in Alzheimer’s disease. (LLM, conf=0.91)

  cites [33] YY Li, 2011, Increased expression of miRNA-146a in alzheimer's disease transgenic mouse models., Neurosci Lett source

In the paper

“Taganov et al (2006) previously showed that TLR2 stimulation by exposure to peptidoglycan and its synthetic analog, Pam3CSK4, produced an up-regulation of miR-146a in human monocytes in contrast to TLR3, TLR7 and TLR9 agonists.”

What the sources say

• Partly supported

  The Results (page not supplied) report that peptidoglycan and Pam3CSK4 induced miR-146 in THP-1 cells, whereas TLR3, TLR7, and TLR9 agonists did not. THP-1 is a human monocytic leukemia cell line, not primary human monocytes; the TLR2 experiment measured miR-146 without distinguishing miR-146a from miR-146b. (LLM, conf=0.88)

  cites Taganov et al (2006) sourceExperimental — accuracy not yet measured

In the paper

“Additionally, like microglial cells, they form spineous processes and express inwardly rectifying, but not outwardly rectifying K+ channels [25].”

What the sources say

• ?Could not verify

  The Introduction identifies BV-2 as a substitute for primary microglia, and the Results discuss inflammatory responses, but neither addresses spineous processes or K+ channel rectification. Searches of our copy for “spineous” and “rectifying” found no passage supporting either feature. (LLM, conf=0.74)

  cites [25] A Henn, 2009, The suitability of BV2 cells as alternative model system for primary microglia cultures or for animal experiments examining brain inflammation., ALTEX sourceExperimental — accuracy not yet measured

In the paper

“This has been previously described in macrophages where miR-146a expression was found to be capable of dampening the immediate innate immune response mediated by TLR2 and TLR4 [16], [30], [31].”

What the sources say

• Partly supported

  The Results show that TLR2 and TLR4 stimuli induce miR-146 expression in THP-1 monocytic cells. The Discussion proposes that miR-146 could reduce TLR signaling, but says its exact role still requires loss-of-function and overexpression studies. It does not establish dampening of an immediate response in macrophages. (LLM, conf=0.88)

  cites [16] KD Taganov, 2006, NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses., Proc Natl Acad Sci U S A sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion reports that miR-146a dampened an IL-1β-induced inflammatory response in human lung epithelial cells. It also notes increased miR-146a expression after activation of monocytes and macrophages, but only suggests that a similar regulatory pathway might operate there. It does not establish that miR-146a dampens macrophage responses mediated specifically by TLR2 and TLR4. Page numbers are unavailable in our copy. (LLM, conf=0.87)

  cites [30] MM Perry, 2008, Rapid changes in microRNA-146a expression negatively regulate the IL-1beta-induced inflammatory response in human lung alveolar epithelial cells., J Immunol sourceExperimental — accuracy not yet measured
• Partly supported

  The Results and Discussion show that miR-146a dampens TLR4-mediated responses to subsequent LPS challenge in THP-1 monocytic cells. They do not demonstrate this effect in macrophages or directly test dampening of TLR2-mediated responses. The Discussion describes TLR2 involvement as a possible extension, while the measured TNF-α response initially rises before miR-146a-associated tolerance develops; page numbers are not available in our copy. (LLM, conf=0.88)

  cites [31] MA Nahid, 2009, miR-146a is critical for endotoxin-induced tolerance: IMPLICATION IN INNATE IMMUNITY., J Biol Chem sourceExperimental — accuracy not yet measured

In the paper

“As is the case in other neurodegenerative conditions, such as Alzheimer's disease, one of the pathological features of disease is the activation of the brain's resident immune cells, the microglia, and the accumulation of astrocytes. In many instances, this feature can be detected prior to clinical symptoms and other signs of neurodegeneration, such as spongiosis and neuronal cell death become app”

What the sources say

• ?Not checked — no full text of the sourcecites [2] A Giese, 1998, Role of microglia in neuronal cell death in prion disease., Brain Pathol source
• ?Could not verify

  The indexed paper discusses Kaposi’s sarcoma herpesvirus signaling, NF-κB activation, and IL-8 secretion (Abstract and Discussion; page numbers unavailable). Searches for prion disease, microglia, astrocytes, and presymptomatic neurodegeneration found no passage addressing the attributed claim. (LLM, conf=0.76)

  cites [3] LW Shepard, 2001, Constitutive activation of NF-kappa B and secretion of interleukin-8 induced by the G protein-coupled receptor of kaposi's sarcoma-associated herpesvirus involve G alpha(13) and RhoA., J Biol Chem sourceExperimental — accuracy not yet measured

In the paper

“In prion disease, microglia appear to express low levels of pro-inflammatory cytokines during chronic neurodegeneration but may be in a “primed” state [8].”

What the sources say

• Supported

  The Background states that microglia express low levels of proinflammatory cytokines during chronic neurodegeneration but are primed to produce more after systemic LPS challenge. The Discussion’s “Exaggerated Sickness Behavior and Microglial Priming” section applies this account to the ME7 model of prion disease. (LLM, conf=0.94)

  cites [8] C Cunningham, 2009, Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease., Biol Psychiatry source

In the paper

“Pathogenic changes in prion disease appear to be independent of MyD88, a signaling intermediate for several TLR family members, as ablation of this molecule did not lead to changes in the incubation periods, and neuropathological profiles of scrapie-infected mice [12].”

What the sources say

• Supported

  The ‘MyD88 -/- mice are highly susceptible to scrapie’ section reports similar incubation times in knockout and wild-type mice and similar vacuolization and reactive astrogliosis. Table 1 (p. 198) notes a slightly longer incubation period after low-dose intraperitoneal challenge, but the text says the difference was not statistically significant. (LLM, conf=0.93)

  cites [12] M Prinz, 2003, Prion pathogenesis in the absence of toll-like receptor signalling., EMBO Rep source

In the paper

“The 3′UTRs of these genes are responsive to interaction with miR-146a, however, regulation was shown to be at the level of translation; mRNA levels remained unchanged.”

What the sources say

• Partly supported

  The Results show that miR-146a reduced expression of reporters bearing the IRAK1 and TRAF6 3′ UTRs, supporting their responsiveness. The paper describes this as posttranscriptional repression, but does not show that repression occurred specifically at translation or that IRAK1 and TRAF6 mRNA levels remained unchanged. (LLM, conf=0.88)

  cites [16] KD Taganov, 2006, NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses., Proc Natl Acad Sci U S A sourceExperimental — accuracy not yet measured

In the paper

“Furthermore, an injection of amyloid into the hippocampus provokes increased TLR2 expression [41].”

What the sources say

• Supported

  The section “TLR2 expression in response to Aβ” reports that injecting Aβ1–42 into the hippocampus of wild-type mice significantly increased TLR2 gene expression compared with saline injection. The claim accurately paraphrases this finding, though the measured expression was TLR2 mRNA. (LLM, conf=0.94)

  cites [41] KL Richard, 2008, Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1–42 and delay the cognitive decline in a mouse model of alzheimer's disease., J Neurosci source

In the paper

“Previously, TRAF6, IRAK1 and IRAK2 have been identified and validated as putative targets of miR-146a in macrophages [16], [37].”

What the sources say

• Partly supported

  The Results report that miR-146a repressed TRAF6 and IRAK1 3′ UTR reporters, supporting their identification as putative targets. The paper does not report IRAK2 as a target, and the target-validation experiments used 293 cells, not macrophages. (LLM, conf=0.90)

  cites [16] KD Taganov, 2006, NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses., Proc Natl Acad Sci U S A sourceExperimental — accuracy not yet measured
• Supported

  The section “miR-146a targets TRAF6, IRAK1, and IRAK2” reports that miR-146a altered TRAF6 and IRAK1 expression in macrophages and presents experimental evidence for IRAK2 targeting. The Discussion explicitly states that the study demonstrated all three to be miR-146a targets in mice. (LLM, conf=0.94)

  cites [37] J Hou, 2009, MicroRNA-146a feedback inhibits RIG-I-dependent type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2., J Immunol source

In the paper

“MiR-146a is also transcribed by NF-κB and therefore may operate as part of a feedback inhibitory regulatory-loop to modulate inflammation by this transcription factor [46].”

What the sources say

• Partly supported

  The Results section reports that HTLV-1 Tax activates the miR-146a promoter through NF-κB. The Discussion proposes a possible negative feedback loop in which miR-146a suppresses NF-κB signaling, but says that loop is inoperative in the HTLV context. Our copy does not establish that the loop modulates inflammation. (LLM, conf=0.87)

  cites [46] K Pichler, 2008, MicroRNA miR-146a and further oncogenesis-related cellular microRNAs are dysregulated in HTLV-1-transformed T lymphocytes., Retrovirology sourceExperimental — accuracy not yet measured

In the paper

“Nevertheless, the study determined by Prinz et al. (2003) showed that MyD88 knock-out mice were readily infectable with scrapie and did not show any significant alteration in the time-course or pathology of the disease [12].”

What the sources say

• Supported

  The section “MyD88 -/- mice are highly susceptible to scrapie” reports that all challenged knockout mice developed scrapie and that their incubation times did not differ significantly from wild-type mice. It also reports similar brain pathology in the two groups; Table 1 (p. 198) notes a slightly longer incubation period at the lower intraperitoneal dose, but the difference was not statistically significant. (LLM, conf=0.94)

  cites [12] M Prinz, 2003, Prion pathogenesis in the absence of toll-like receptor signalling., EMBO Rep source

In the paper

“Interestingly, this gene has been shown to be targeted by miR-146a and down-regulated in Alzheimer's disease as well as in other diseases such as Herpes simplex virus type1 infection [47], [48].”

What the sources say

• Partly supported

  Figure 5 (p. 31319) reports that CFH, described as a miR-146a target, is down-regulated in Alzheimer disease brain. The discussion also links increased miR-146a to reduced CFH expression, but our copy does not address herpes simplex virus type 1 infection (searched: “Herpes simplex virus type 1 infection” and “HSV-1 viral infection”). (LLM, conf=0.88)

  cites [47] WJ Lukiw, 2008, An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in alzheimer disease and in stressed human brain cells., J Biol Chem sourceExperimental — accuracy not yet measured
• Supported

  The Results report that CFH was reduced 4.5-fold in HSV-1-infected human neural cells. The Conclusion identifies CFH as a known miR-146a target. This source supports the HSV-1 portion of the sentence; the Alzheimer's disease portion is not assigned specifically to it in the two-citation sentence. (LLM, conf=0.92)

  cites [48] JM Hill, 2009, HSV-1 infection of human brain cells induces miRNA-146a and alzheimer-type inflammatory signaling., Neuroreport source

In the paper

“The gene IL-1B has previously been reported to be negatively regulated by miR-146a [30].”

What the sources say

• Partly supported

  The Introduction and Discussion report that miR-146a negatively regulates the inflammatory response induced by IL-1β, including IL-8 and RANTES release. They do not report negative regulation of the IL-1B gene itself; the Results instead describe IL-1β stimulation increasing miR-146a expression. Page numbers were not provided in our copy. (LLM, conf=0.84)

  cites [30] MM Perry, 2008, Rapid changes in microRNA-146a expression negatively regulate the IL-1beta-induced inflammatory response in human lung alveolar epithelial cells., J Immunol sourceExperimental — accuracy not yet measured

In the paper

“Previous studies have determined that miR-146a can regulate NF-κB itself, as well as key genes downstream of NF-κB [16].”

What the sources say

• Partly supported

  The Results show that miR-146a represses reporters bearing the IRAK1 and TRAF6 3′ UTRs, and the Discussion proposes that this could reduce NF-κB pathway activity through negative feedback. But the paper describes IRAK1 and TRAF6 as mediators of NF-κB activation, not genes downstream of NF-κB; it also does not show direct regulation of NF-κB itself. No page numbers are available in our copy. (LLM, conf=0.86)

  cites [16] KD Taganov, 2006, NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses., Proc Natl Acad Sci U S A sourceExperimental — accuracy not yet measured

In the paper

“Additionally, a number of miRNAs found to be up-regulated in a recent study profiling glial cells in multiple sclerosis brain lesions, as well as our previous study to determine deregulated miRNAs in scrapie infection, were also identified to be enriched in microglial cell lines in this study [18], [38]. These were miR-142-3p, miR-34a, and miR-223.”

What the sources say

• ?Could not verify

  The Materials and Methods and Results describe gene-expression measurements in irradiated human lymphoblastoid cell lines, not microglial or multiple-sclerosis glial cells. Searches for the three named miRNAs, microglia, multiple sclerosis, and scrapie found no passage addressing their enrichment or up-regulation. The cited paper therefore cannot verify the attributed claim. (LLM, conf=0.78)

  cites [18] VG Tusher, 2001, Significance analysis of microarrays applied to the ionizing radiation response., Proc Natl Acad Sci U S A sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [38] A Junker, 2009, MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47., Brain source

In the paper

“Caspase-8 is known to have non-apoptotic functions and has been shown to be required for TLR signaling and in the regulation of NF-κB function [36].”

What the sources say

• Supported

  The paper’s abstract explicitly describes non-apoptotic functions for caspase-8 and its requirement for TLR signaling and regulation of NF-κB function. The Discussion (pp. 7421–7422) specifies that the findings concern B-cell responses to TLR2, TLR3 and TLR4, with delayed rather than blocked NF-κB signaling after TLR4 stimulation. (LLM, conf=0.95)

  cites [36] B Lemmers, 2007, Essential role for caspase-8 in toll-like receptors and NFkappaB signaling., J Biol Chem source

In the paper

“While the BV-2 cell line divided very rapidly, at least once during a 24 hour period, EOC 13.31 cells doubled only every 48 hours.”

In the paper

“Other receptors including Fc (FCGR1 and FCGR3) and complement receptors (ITGAM and ITGAX), as well as TREM2 a myeloid specific receptor triggered by amyloid to promote active phagocytosis, were also found to be over-expressed.”

In the paper

“However, the mRNAs of other TLRs, including TLR4, were barely detectable in our study and so we could not determine whether there was an increase in expression of these receptors in the infected animals.”

In the paper

“This treatment, in turn, prevented the induction of miR-146a in EOC 13.31 cells stimulated via the crude LPS preparation, but not similarly treated BV-2 cells (Figure 2C).”

In the paper

“Agonist treatment uniformly resulted in the significant induction of miR-146a expression that increased over time to a maximum at 48 hours post-stimulation, but was still elevated even at 72 hours post stimulation (Figure 3).”

In the paper

“All three were found to peak well before 24 hours post-stimulation and had all returned to basal levels by 48 hours (Figure 3).”

In the paper

“In situ hybridization to detect miR-146a expression proved inconclusive in confirming this (data not shown).”

In the paper

“Other groups of up-regulated genes included genes involved in cell cycle progression, cell death, cellular movement and morphology.”

In the paper

“The transcription regulator SMAD3 was identified as a potential target of miR-146a in both resting cells and those stimulated with LPS and has not been described to be a target of miR-146a.”

In the paper

“A significant number of genes were de-regulated under these conditions, 22 (3 down-regulated, 19 up-regulated) at 8 hours post transfection and 977 (778 down-regulated, 199 up-regulated) at 24 hours.”

In the paper

“Our first finding was that in contrast to the rapid and transient induction of transcription of inflammatory mediators such as cytokines IL-6 and TNF, miR-146a expression follows alternate kinetics. MiR-146a was induced at a slower rate, reaching a peak after 24 hours that is maintained even at 48 and 72 hours post-stimulation; time-points when cytokine expression levels have returned to base-line”

In the paper

“Examination of the ontologies enriched in this set of up-regulated genes showed genes known to play a role in infection processes, including NR3C1, PTPRC, SFRS1, SFRS5, SMAD3, C3 and DDX58.”

In the paper

“A number of important transcriptional regulators PAX6, MDM2, JAK2 and SMAS3 were increased, as were some caspases, CASP7 and CASP8, and the apoptotic regulator BCL2L1.”

In the paper

“Ribosomal proteins were strikingly up-regulated resulting in a significance score in IPA of p = 1.13×10−54, similarly numerous mitochondrial cytochrome C oxidase subunits involved in oxidative phosphorylation were also up-regulated.”

In the paper

“One up-regulated cytokine coding gene was IL-10, a negative regulator of cytokine production during the immune response; however, this gene was expressed at very low levels based on the spot intensity observed by microarray and we were unable to detect IL-10 expression by ELISA.”

In the paper

“Indeed, we did find a significant number of up-regulated genes at 8 hours (691 annotated genes), with a smaller number (354 annotated genes) up-regulated at 24 hours post stimulation.”

In the paper

“The mRNA levels of IRAK1 were similarly found to be unchanged in our study, although we measured a small, but significant, down-regulation of TRAF6 gene expression in EOC 13.31 cells transfected with a miR-146a mimic.”

In the paper

“These included the genes NOS1, NOS2 and NOS3, nitric oxide synthases that are inducible by TLR stimulation and NOX4, a gene involved in H2O2 production. Significantly, the genes CYBA and CYBB proposed to be primary components of the microbicidal oxidase system of phagocytes, were also down-regulated, as was SOD3. SOD1, however, was up-regulated in our work.”

In the paper

“In particular, IL-1B, a key mediator of the inflammatory response, is both down-regulated following miR-146a over-expression and up-regulated after knock-down.”

In the paper

“In subsequent studies using TaqMan® qRT-PCR assays we have found that miR-146a is expressed at low levels in laser capture microdissected (LCM) neurons isolated from mouse hippocampus (data not shown)”

In the paper

“This includes the down-regulation of the cytokine IL-1B by miR-146a over-expression and up-regulation following knock-down.”

In the paper

“Substantially fewer genes were dysregulated following transfection of miR-146a anti-miR and these were for the most part up-regulated.”

In the paper

“Firstly, we confirmed that miR-146a is over-expressed in the brain's of mice during scrapie infection and that this expression is, most likely, highly enriched in cells of microglial origin based on miRNA expression profiling of various brain-derived cell lines.”

In the paper

“Interestingly, IL-1B appeared to be tightly regulated by miR-146a; its expression is decreased following transfection of the miR-146a mimic and increased following knock-down with an anti-miR in both resting and TLR-stimulated cells.”

In the paper

“Over-expression was achieved by transfecting 30 nM of miR-146a mimic (Figure 4A).”

In the paper

“All procedures involving live animals were approved by the Canadian Science Centre for Human and Animal Health - Animal Care Committee (CSCHAH-ACC).”

In the paper

“MiRNA expression was normalized to the U6 snRNA level which was expressed at high levels with negligible variance under the experimental conditions used in our study.”

In the paper

“Un-methylated CpG DNA, which is an agonist of TLR9 signaling, has been shown to prolong the scrapie incubation period in mice, suggesting that innate immune activation can interfere with prion disease progression [9], [10].”

What the sources say

• ?Not checked — no full text of the sourcecites [9] S Sethi, 2002, Postexposure prophylaxis against prion disease with a stimulator of innate immunity., Lancet source
• ?Not checked — no full text of the sourcecites [10] DS Spinner, 2007, CpG oligodeoxynucleotide-enhanced humoral immune response and production of antibodies to prion protein PrPSc in mice immunized with 139A scrapie-associated fibrils., J Leukoc Biol source

In the paper

“Signaling pathways involving NF-κB, JNK and MAPK are implicated in Figure 6B.”

In the paper

“This data implies that TLR2-signaling is not essential to the disease process and that our model may not mimic processes that occur during disease.”

In the paper

“Conversely, we found a small number of genes to increase in expression upon transfection of a miR-146a mimic. One of these was IL-10, an anti-inflammatory cytokine that can down-regulate the expression of cytokines, MHC class II molecules, and co-stimulatory molecules on macrophages, and has been found to be up-regulated in human patients with CJD [50].”

What the sources say

• ?Not checked — no full text of the sourcecites [50] K Stoeck, 2006, Pro- and anti-inflammatory cytokines in the CSF of patients with creutzfeldt-jakob disease., J Neuroimmunol source

In the paper

“In terms of prion disease this suggests the considerable increase in expression of TLR2 observed at clinical stages of prion disease could be indicative of the accumulation of microglia that are not in an activation state that is optimal for phagocytosis. This could therefore contribute to defective clearing of debris and prion accumulation during later stages of disease.”

In the paper

“Cells lacking these receptors could not initiate a Src-Vav-Rac signaling cascade required to stimulate phagocytosis of amyloid beta deposits [45].”

What the sources say

• Not checked yetcites [45] GE Landreth, 2009, Toll-like receptors in alzheimer's disease., Curr Top Microbiol Immunol

In the paper

“Interestingly TLR2, and TLR7 which was also up-regulated in our prion model, has also been shown to display profoundly increased expression levels in APP transgenic mice that accumulate amyloid deposits in their brain [40].”

What the sources say

• ?Not checked — no full text of the sourcecites [40] M Letiembre, 2009, Screening of innate immune receptors in neurodegenerative diseases: A similar pattern., Neurobiol Aging source

In the paper

“It has also been reported by others that TLR 2, 4, and 9 signaling modulates phacogytosis and clearance of neurotoxic amyloid deposition in neurodegenerative diseases, perhaps by MyD88 independent signaling pathways [43], [55].”

What the sources say

• ?Not checked — no full text of the sourcecites [43] P Iribarren, 2005, CpG-containing oligodeoxynucleotide promotes microglial cell uptake of amyloid beta 1–42 peptide by up-regulating the expression of the G-protein- coupled receptor mFPR2., FASEB J source
• ?Not checked — no full text of the sourcecites [55] K Tahara, 2006, Role of toll-like receptor signalling in abeta uptake and clearance., Brain source

In the paper

“confirming very high reproducibility of the microarray data.”

In the paper

“They are also highly related based on potential interactions identified using the IPA tool, potentially a co-ordinately regulated gene set.”

In the paper

“In addition, NOS2, QK1 and BCL2L1 are also predicted from this study as being strong candidates for targeting by miR-146a that have not previously been described.”

In the paper

“Landreth and Reed-Geaghan (2009) have also shown that the response of microglia to fibrillar Aβ is reliant upon the expression of TLR4, TLR2 and the co-receptor CD14 to activate intracellular signaling [45].”

What the sources say

• Not checked yetcites [45] GE Landreth, 2009, Toll-like receptors in alzheimer's disease., Curr Top Microbiol Immunol

In the paper

“SMAD3 knock-out mice exhibit alterations in many aspects of glial function, including altered scar formation and immune response to injury [51]. Fewer neutrophils, macrophages/microglia, NG2-positive cells and GFAP-positive cells were reported around lesions in Smad3 null mice brains.”

What the sources say

• ?Not checked — no full text of the sourcecites [51] Y Wang, 2007, Smad3 null mice display more rapid wound closure and reduced scar formation after a stab wound to the cerebral cortex., Exp Neurol source

In the paper

“Not only are genes involved in cytokine and other aspects of the inflammatory response regulated by its expression, but we found in this study that genes involved in morphological changes that accompany activation, chemotaxis and oxidative burst-related genes may also be targets for either direct or indirect miR-146a regulation.”

In the paper

“This discrepancy is very likely multi-factorial and contributing factors include, but are certainly not limited to, lack of multiple cell types and associated cell-to-cell signaling in in vitro culture, lack of normal cellular functions under in vitro conditions, and also the time required for disease progression, which is often months to years in whole organism/animal.”

In the paper

“Transfected anti-miRs or mimics were stably detected over a 24–48 hour period post transfection; therefore cells were transfected and allowed to recover overnight, thus reducing the likelihood of differential expression induced by the transfection process, prior to stimulation.”