Signaling through MyD88 Regulates Leukocyte Recruitment after Brain Injury

Babcock, Alicia; Toft-Hansen, Henrik; Owens, Trevor

doi:10.4049/jimmunol.181.9.6481

Cited by 59 publications

(46 citation statements)

References 82 publications

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“…This experimental design was based on the following four lines of evidence: only 5.65 6 2.66% microglia in the hippocampus were derived from BM cells in the TgCRND8 APP-transgenic mice 3 mo post-BM reconstruction, whose heads were protected during irradiation (Y. Liu, W. Hao, and K. Fassbender, unpublished observations); TLR2 did not affect the recruitment of microglia into the brain in the wild-type mice after whole-body irradiation (Fig. 6B); TLR2 does not regulate leukocyte recruitment after brain injury (44); and sufficient BM-derived microglia can be recruited to Ab deposits in BMreconstructed APP-transgenic mice after whole-body irradiation (19,39,45). The animal model could not have been constructed by cross-breeding TLR2-deficient and APP-transgenic mice, because TLR2 expression in neurons (46) would have made it impossible to distinguish TLR2 effects from microglia and TLR2 effects from nonmicroglial cells in AD animals with an overall deficiency in TLR2.…”

Section: Discussionmentioning

confidence: 98%

TLR2 Is a Primary Receptor for Alzheimer’s Amyloid β Peptide To Trigger Neuroinflammatory Activation

Liu

Hao

et al. 2012

The Journal of Immunology

357

259

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Microglia activated by extracellularly deposited amyloid β peptide (Aβ) act as a two-edged sword in Alzheimer’s disease pathogenesis: on the one hand, they damage neurons by releasing neurotoxic proinflammatory mediators (M1 activation); on the other hand, they protect neurons by triggering anti-inflammatory/neurotrophic M2 activation and by clearing Aβ via phagocytosis. TLRs are associated with Aβ-induced microglial inflammatory activation and Aβ internalization, but the mechanisms remain unclear. In this study, we used real-time surface plasmon resonance spectroscopy and conventional biochemical pull-down assays to demonstrate a direct interaction between TLR2 and the aggregated 42-aa form of human Aβ (Aβ42). TLR2 deficiency reduced Aβ42-triggered inflammatory activation but enhanced Aβ phagocytosis in cultured microglia and macrophages. By expressing TLR2 in HEK293 cells that do not endogenously express TLR2, we observed that TLR2 expression enabled HEK293 cells to respond to Aβ42. Through site-directed mutagenesis of tlr2 gene, we identified the amino acids EKKA (741–744) as a critical cytoplasmic domain for transduction of inflammatory signals. By coexpressing TLR1 or TLR6 in TLR2-transgenic HEK293 cells or silencing tlrs genes in RAW264.7 macrophages, we observed that TLR2-mediated Aβ42-triggered inflammatory activation was enhanced by TLR1 and suppressed by TLR6. Using bone marrow chimeric Alzheimer’s amyloid precursor transgenic mice, we observed that TLR2 deficiency in microglia shifts M1- to M2-inflammatory activation in vivo, which was associated with improved neuronal function. Our study demonstrated that TLR2 is a primary receptor for Aβ to trigger neuroinflammatory activation and suggested that inhibition of TLR2 in microglia could be beneficial in Alzheimer’s disease pathogenesis.

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Section: Discussionmentioning

confidence: 98%

TLR2 Is a Primary Receptor for Alzheimer’s Amyloid β Peptide To Trigger Neuroinflammatory Activation

Liu

Hao

et al. 2012

The Journal of Immunology

357

259

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“…The transection of projections from entorhinal cortex to the hippocampus leads to anterograde axonal degeneration and loss of synapses in the outer molecular layer of the dentate gyrus, followed by glial activation, leukocyte infiltration, and sprouting (13)(14)(15)(16)(17)(18)(19)(20). Involvement of TLR signaling as well as cytokines (TNF-a and IL-1b) and chemokines (CCL2 and CXCL10) in glial response and recruitment of leukocytes in the lesion-reactive hippocampus have been described previously (15,17,21,22). We previously described glial upregulation of STAT1 and STAT2 (21), which suggested the involvement of type I IFN signaling.…”

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confidence: 83%

Injury-Induced Type I IFN Signaling Regulates Inflammatory Responses in the Central Nervous System

Khorooshi

Owens

2010

The Journal of Immunology

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Innate glial response is critical for the induction of inflammatory mediators and recruitment of leukocytes to sites of the injury in the CNS. We have examined the involvement of type I IFN signaling in the mouse hippocampus following sterile injury (transection of entorhinal afferents). Type I IFNs signal through a receptor (IFNAR), which involves activation of IFN regulatory factor (IRF)9, leading to the induction of IFN-stimulated genes including IRF7, that in turn enhances the induction of type I IFN. Axonal transection induced upregulation of IRF7 and IRF9 in hippocampus. Induction of IRF7 and IRF9 mRNAs was IFNAR dependent. Double-labeling immunofluorescence showed that IRF7 selectively was induced in Mac-1/CD11b+ macrophages/microglia in hippocampus after axonal transection. IRF7 mRNA was also detected in microglia sorted by flow cytometry. Lack of type I IFN signaling resulted in increased leukocyte infiltration into the lesion-reactive hippocampus. Axonal lesion-induced CXCL10 gene expression was abrogated, whereas matrix metalloproteinase 9 mRNA was elevated in IFNAR-deficient mice. Our findings point to a role for type I IFN signaling in regulation of CNS response to sterile injury.

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“…Iba-1-and GFAP-immunofluorescent areas were measured using LSM5 PASCAL software (Carl Zeiss) and expressed as the area (m 2 /10,000 m 2 ). Flow Cytometry-For flow cytometry analysis of microglia and macrophages, the ipsilateral hippocampi of WT and TLR2 KO mice were carefully dissected and dissociated as previously described (31). Briefly, a single-cell suspension was prepared and fixed with 2% paraformaldehyde.…”

Section: Methodsmentioning

confidence: 99%

“…We differentiated these two cell populations by flow cytometry. Upon KA activation, the number of CD11b ϩ /CD45 low cells representing the microglia population (31) in WT mice increased to 25%, whereas it increased only to 17% in TLR2 KO mice (Fig. 4, …”

Section: Ka-induced Microglia Activation Is Reduced In Tlr2 Ko Mice mentioning

confidence: 97%

Microglial Toll-like Receptor 2 Contributes to Kainic Acid-induced Glial Activation and Hippocampal Neuronal Cell Death

Hong

Cho

Kwak

et al. 2010

Journal of Biological Chemistry

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Recent studies indicate that Toll-like receptors (TLRs), originally identified as infectious agent receptors, also mediate sterile inflammatory responses during tissue damage. In this study, we investigated the role of TLR2 in excitotoxic hippocampal cell death using TLR2 knock-out (KO) mice. TLR2 expression was up-regulated in microglia in the ipsilateral hippocampus of kainic acid (KA)-injected mice. KA-mediated hippocampal cell death was significantly reduced in TLR2 KO mice compared with wild-type (WT) mice. Similarly, KA-induced glial activation and proinflammatory gene expression in the hippocampus were compromised in TLR2 KO mice. In addition, neurons in organotypic hippocampal slice cultures (OHSCs) from TLR2 KO mouse brains were less susceptible to KA excitotoxicity than WT OHSCs. This protection is partly attributed to decreased expression of proinflammatory genes, such as TNF-␣ and IL-1␤ in TLR2 KO mice OHSCs. These data demonstrate conclusively that TLR2 signaling in microglia contributes to KA-mediated innate immune responses and hippocampal excitotoxicity.Toll-like receptors (TLRs) 3 are a group of transmembrane proteins that play a central role in innate immune responses.To date, more than 10 different TLR members have been identified that each recognizes a specific set of pathogen-associated molecular patterns (PAMPs) expressed by microorganisms (1, 2). Interestingly, emerging data indicate that TLRs function as receptors not only for PAMPs, but also for endogenous molecules released from damaged tissue or cells. For example, TLR2 and -4 recognize various endogenous molecules including heat shock proteins, hyaluronan, and high mobility group box-1 (HMGB-1) (3-6). In addition, TLR3 binds mRNA released from necrotic cells (7). It is possible that TLR recognition of these endogenous molecules is involved in the inflammatory response during "sterile" tissue damage.In the central nervous system (CNS), TLRs including TLR2, -3, and -4 are expressed in microglia and astrocytes, suggesting a role as innate immune cells in the CNS (8). Based on their function as receptors for "danger signals" (9), TLR expression in glial cells is implicated in various "sterile" neurological disorders including mouse cerebral ischemia/reperfusion injury (10, 11), spinal cord injury (12), and axonal transection (13). We have also reported that TLR2 plays a critical role in nerve injury-induced spinal cord glial activation and subsequent pain hypersensitivity (14), and traumatic brain injury (15). In mouse epileptic seizure model, TLR2 transcripts are up-regulated in hippocampal microglia/ macrophages upon pilocarpine injection (16) implicating TLR2 in hippocampal excitotoxicity, although this possibility has not yet been explored.Excitotoxicity is an underlying mechanism of various neurological disorders including traumatic brain injury and stroke, and is also implicated in chronic neurodegenerative diseases such as amyotrophic lateral sclerosis and epileptic seizure (17). NMDA and AMPA/kainate glutamate receptor overstimu...

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Signaling through MyD88 Regulates Leukocyte Recruitment after Brain Injury

Cited by 59 publications

References 82 publications

TLR2 Is a Primary Receptor for Alzheimer’s Amyloid β Peptide To Trigger Neuroinflammatory Activation

TLR2 Is a Primary Receptor for Alzheimer’s Amyloid β Peptide To Trigger Neuroinflammatory Activation

Injury-Induced Type I IFN Signaling Regulates Inflammatory Responses in the Central Nervous System

Microglial Toll-like Receptor 2 Contributes to Kainic Acid-induced Glial Activation and Hippocampal Neuronal Cell Death

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