TLR2 and Caspase-8 Are Essential for Group B<i>Streptococcus</i>-Induced Apoptosis in Microglia

Lehnardt, Seija; Wennekamp, Julia; Freyer, Dorette; Liedtke, Christian; Krueger, Christina; Nitsch, Robert; Bechmann, Ingo; Weber, Joerg R.; Henneke, Philipp

doi:10.4049/jimmunol.179.9.6134

Cited by 46 publications

(40 citation statements)

References 73 publications

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“…This observation is indicative of a mode of neurodegeneration that may contribute to the disease process of GBS meningitis in neonates [17]. Furthermore GBS can trigger microglial apoptosis in a pathway dependent upon TLR2 and caspase 8 [101]. A functional interaction between TLR2 and GBS is consistent with other studies which indicate that TLR2 is required for host defence against GBS in other disease settings such as arthritis and sepsis [102].…”

Section: Tlrs In Response To Bacterial Meningitissupporting

confidence: 86%

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

Carty

Bowie

2011

Biochemical Pharmacology

134

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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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Section: Tlrs In Response To Bacterial Meningitissupporting

confidence: 86%

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

Carty

Bowie

2011

Biochemical Pharmacology

134

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“…9. Such functions of these molecules may be useful to protect cells from strong extracellular stimuli or cytotoxic signaling because the MyD88-dependent signaling pathway is cytotoxic under certain cellular circumstances (12,32,33).…”

Section: Discussionmentioning

confidence: 99%

Regulation of MyD88 Aggregation and the MyD88-dependent Signaling Pathway by Sequestosome 1 and Histone Deacetylase 6

Into

Inomata

Niida

et al. 2010

Journal of Biological Chemistry

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MyD88 is an essential adaptor molecule for Toll-like receptors (TLRs) and interleukin (IL)-1 receptor. MyD88 is thought to be present as condensed forms or aggregated structures in the cytoplasm, although the reason has not yet been clear. Here, we show that endogenous MyD88 is present as small speckle-like condensed structures, formation of which depends on MyD88 dimerization. In addition, formation of large aggregated structures is related to cytoplasmic accumulation of sequestosome 1 (SQSTM1; also known as p62) and histone deacetylase 6 (HDAC6), which are involved in accumulation of polyubiquitinated proteins. A gene knockdown study revealed that SQSTM1 and HDAC6 were required for MyD88 aggregation and exhibited a suppressive effect on TLR ligand-induced expression of IL-6 and NOS2 in RAW264.7 cells. SQSTM1 and HDAC6 were partially involved in suppression of several TLR4-mediated signaling events, including activation of p38 and JNK, but they hardly affected degradation of IB␣ (inhibitor of nuclear factor B). Biochemical induction of MyD88 oligomerization induced recruitment of SQSTM1 and HDAC6 to the MyD88-TRAF6 signaling complex. Repression of SQSTM1 and HDAC6 enhanced formation of the MyD88-TRAF6 complex and conversely decreased interaction of the ubiquitin-specific negative regulator CYLD with the complex. Furthermore, ubiquitin-binding regions on SQSTM1 and HDAC6 were essential for MyD88 aggregation but were not required for interaction with the MyD88 complex. Thus, our study reveals not only that SQSTM1 and HDAC6 are important determinants of aggregated localization of MyD88 but also that MyD88 activates a machinery of polyubiquitinated protein accumulation that has a modulatory effect on MyD88-dependent signal transduction. MyD88 was originally identified as an inducible protein during terminal differentiation of M1 myeloleukemic cells upon interleukin (IL)-6 stimulation (1). The essential function ofMyD88 was later revealed to be a universal adaptor molecule for type 1 IL-1 receptor (IL-1R) 2 and Toll-like receptors (TLRs) (2-4). MyD88 is composed of three distinct regions, an N-terminal death domain, an intermediary domain, and a Toll/IL-1 homology domain at the C terminus (5). After receptor ligation, MyD88 interacts with the Toll/IL-1 homology domain of IL-1R/TLRs and then activates the signaling pathway through dimerization and utilizing death domain-containing IL-1R-associated kinases (2, 6, 7). This pathway is further activated through the ubiquitin E3 ligase TRAF6 (tumor necrosis factor (TNF) receptor-associated factor 6) that works together with a ubiquitin-conjugating enzyme complex consisting of UBC13 and UEV1A to catalyze Lys 63 -linked polyubiquitination, which then activates the TAK1 kinase. TAK1 activates IB kinases and cascades of mitogen-activated protein kinases (MAPKs), ultimately leading to early phase activation of nuclear factor (NF)-B and AP-1 and the transcription of genes encoding various proinflammatory mediators, such as TNF, NOS2 (nitricoxide synthase 2), and IL-6 (6, 7).In ...

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“…The TLR4 triggers microglial apoptosis via autocrine production of IFN-␥, whereas TLR2 is coupled to caspase-8-dependent apoptotic pathways (514). Similarly, TLR2 receptors were instrumental for microglial apoptosis following HIV-1 infection (20,21).…”

Section: A Toll-like Receptorsmentioning

confidence: 99%

Physiology of Microglia

Kettenmann

Hanisch

Нода

et al. 2011

Physiological Reviews

3,134

2,981

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Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed “resting microglia.” Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the “activated microglial cell.” This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

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TLR2 and Caspase-8 Are Essential for Group BStreptococcus-Induced Apoptosis in Microglia

Cited by 46 publications

References 73 publications

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

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

Regulation of MyD88 Aggregation and the MyD88-dependent Signaling Pathway by Sequestosome 1 and Histone Deacetylase 6

Physiology of Microglia

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