Key Role of CD36 in Toll-Like Receptor 2 Signaling in Cerebral Ischemia

Abe, Takato; Shimamura, Munehisa; Jackman, Katherine; Kurinami, Hitomi; Anrather, Josef; Zhou, Ping; Iadecola, Costantino

doi:10.1161/strokeaha.109.572552

Cited by 107 publications

(93 citation statements)

References 28 publications

(55 reference statements)

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“…By analogy, we suggest that CD36 may play a supportive role in the detection of KOdiA-PC by an unknown signal transduction receptor(s). Indeed, CD36 is a cofactor of the toll-like receptor 2 and enhances recognition of lipoteichoic acid by this receptor (2). It should be noted that mice did not hesitate to ingest the fluid containing 7.5 μM KOdiA-PC at the first trial but did hesitate at the second and third trials ( Fig.…”

Section: The Effect Of Onx On Kodia-pc Perception In Micementioning

confidence: 90%

A role of CD36 in the perception of an oxidised phospholipid species in mice

et al. 2015

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CD36 is a broadly expressed transmembrane protein that engages multiple ligands, including polar lipids. This protein is thought to even contribute to the chemosensory detection of long-chain fatty acids in the oral cavity of rodents. In this study, we assessed whether animals consciously perceive a ligand of CD36, 1-(palmitoyl)-2-(5-keto-6-octanedioyl)phosphatidylcholine (KOdiA-PC), and if so, whether CD36 is involved in sensing the oxidised phospholipid species. We found that mice avoided or hesitated to ingest fluids containing KOdiA-PC, suggesting a conscious perception of the lipid in the animals. We assessed the involvement and role of CD36 in the KOdiA-PC perception by comparing the behavioural responses of wild-type and CD36-deficient mice to the test fluids, and provided evidence that the protein could play a role in sensing a lower level of the lipid. We also found that transection of the olfactory nerve of wild-type mice resulted in an inability to perceive KOdiA-PC, suggesting the significance of olfactory system in the lipid sensing. Our findings, coupled with the recent finding of CD36 expression in the mouse olfactory epithelium, led us to predict that the site of CD36 action in the KOdiA-PC sensing plausibly lies within the nasal cavity of the animal.Animals have highly developed chemosensory systems that enable efficient detection of diverse soluble or volatile molecules. Detection of exogenous molecules by taste bud cells and/or olfactory receptor cells transmits signals to the brain and consequently induces various behavioural responses (e.g., appetitive or aversive response to foods) (21, 25). To better understand the mechanisms underlying chemosensory perception, much effort has gone into identifying sensory proteins in the oral and nasal cavities (4, 5). CD36 is a broadly expressed transmembrane protein associated with the recognition of multiple molecules (e.g., amphipathic lipids) (15,19). For instance, in macrophages, CD36 contributes to the clearance of oxidised forms of low-density lipoprotein from the blood by recognising distinct phospholipid species on the surface of the particles (6,20). Furthermore, CD36 expressed by enterocytes is believed to participate in not only recognition and absorption of long-chain fatty acids but also in formation of chylomicrons (18). In addition to its well-characterized functions, CD36 has been postulated to play an important role in the chemosensory detection of longchain fatty acids in the oral cavity, leading to an appetitive response to the lipid species in rodents. Several lines of evidence support this finding: CD36 is localised to the apical surface of taste bud cells in

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Section: The Effect Of Onx On Kodia-pc Perception In Micementioning

confidence: 90%

A role of CD36 in the perception of an oxidised phospholipid species in mice

et al. 2015

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“…The scavenger receptor CD36 is a coreceptor for TLR1/2 and TLR2/6 heterodimers and cerebral injection of ligands for TLR1/2, but not ligands for TLR2/6 or TLR4, produced an inflammatory response that was dependent on CD36. This indicates that CD36 is necessary for TLR1/2 signalling in the brain [65] (Table 2).…”

Section: Page 18 Of 62mentioning

confidence: 96%

“…This protective effect was shown to be dependent upon TLR4 to upregulate TNFα, inducible NO synthase, cyclooxygenase 2 and NFκB [68]. M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 …”

Section: Tlrs In Neuroprotectionmentioning

confidence: 99%

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Evaluating the role of Toll-like receptors in diseases of the central nervous system

Carty

Bowie

2011

Biochemical Pharmacology

132

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A key part of the innate immune system is a network of pattern recognition receptors (PRRs) and their associated intracellular signalling pathways. Toll-like receptors (TLRs) are one such group of PRRs that detect pathogen associated molecular patterns (PAMPs). Activation of the TLRs with their respective agonists results in the activation of intracellular signalling pathways leading to the expression of proinflammatory mediators and anti-microbial effector molecules. Activation of the innate immune system through TLRs also triggers the adaptive immune response, resulting in a comprehensive immune program to eradicate invading pathogens. It is now known that immune surveillance and inflammatory responses occur in the central nervous system (CNS). Furthermore it is becoming increasingly clear that TLRs have a role in such CNS responses andare also implicated in the pathogenesis of a number of conditions in the CNS, such as Alzheimer's, stroke and multiple sclerosis. This is likely due to the generation of endogenous TLR agonists in these conditions which amplifies a detrimental neurotoxic inflammatory response. However TLRs in some situations can be neuroprotective, if triggered in a favourable context. This review aims to examine the recent literature on TLRs in the CNS thus demonstrating their importance in a range of infectious and non-infectious diseases of the brain.

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“…As TLR2 activation triggers a further release of inflammatory factors, a self-sustaining inflammatory loop may be generated in the brain and may explain glial long-term activation (10,11,19,27). In brain, TLR2 upregulation has indeed been observed in several CNS disease states (6,26,(28)(29)(30) and may be functionally involved in the damage generation (22)(23)(24)(31)(32)(33)(34)(35).…”

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confidence: 99%

TLR2 Hypersensitivity of Astrocytes as Functional Consequence of Previous Inflammatory Episodes

Henn

Kirner

Leist

2011

The Journal of Immunology

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Precedent inflammatory episodes may drastically modify the function and reactivity of cells. We investigated whether priming of astrocytes by microglia-derived cytokines alters their subsequent reaction to pathogen-associated danger signals not recognized in the quiescent state. Resting primary murine astrocytes expressed little TLR2, and neither the TLR2/6 ligand fibroblast-stimulating lipopeptide-1 (FSL1) nor the TLR1/2 ligand Pam3CysSK4 (P3C) triggered NF-κB translocation or IL-6 release. We made use of single-cell detection of NF-κB translocation as easily detectable and sharply regulated upstream indicator of an inflammatory response or of c-Jun phosphorylation to measure restimulation events in astrocytes under varying conditions. Cells prestimulated with IL-1β, with a TLR3 ligand, with a complete cytokine mix consisting of TNF-α, IL-1β, and IFN-γ, or with media conditioned by activated microglia responded strongly to FSL1 or P3C stimulation, whereas the sensitivity of the NF-κB response to other pattern recognition receptors was unchanged. This sensitization to TLR2 ligands was associated with an initial upregulation of TLR2, displayed a “memory” window of several days, and was largely independent of the length of prestimulation. The altered signaling led to altered function, as FSL1 or P3C triggered the release of IL-6, CCL-20, and CXCL-2 in primed cells, but not in resting astrocytes. These data confirmed the hypothesis that astrocytes exposed to activated microglia assume a different functional phenotype involving longer term TLR2 responsiveness, even after the initial stimulation by inflammatory mediators has ended.

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Key Role of CD36 in Toll-Like Receptor 2 Signaling in Cerebral Ischemia

Cited by 107 publications

References 28 publications

<b>A role of CD36 in the perception of an oxidised phospholipid species in </b><b>mice </b>

<b>A role of CD36 in the perception of an oxidised phospholipid species in </b><b>mice </b>

Evaluating the role of Toll-like receptors in diseases of the central nervous system

TLR2 Hypersensitivity of Astrocytes as Functional Consequence of Previous Inflammatory Episodes

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