Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia

Lehnardt, Seija; Lehmann, Sabrina; Kaul, David; Tschimmel, Katharina; Hoffmann, Olaf; Cho, Sabine; Krueger, Christina; Nitsch, Robert; Meisel, Andreas; Weber, Joerg R.

doi:10.1016/j.jneuroim.2007.07.023

Cited by 237 publications

(223 citation statements)

References 21 publications

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“…Indeed, in our current study TLR2−/− neonatal mice demonstrated delayed clearance of S. epidermidis from the bloodstream, spleen, and liver. In addition to its important roles in host defense in clearing bacteria, TLR2 may mediate some forms of inflammatory brain injury [42], including middle cerebral artery occlusion [43] and neonatal hypoxia-ischemiainduced brain injury [44]. Indeed, consistent with the known role of TLR2 in mediating neuroinflammation and neuronal damage [45], we have previously demonstrated that a single intraperitoneal injection of the TLR2 agonist Pam 3 CSK 4 revealed a robust increase in the WBC count in the CSF in mice on PND8 [38], and repeated administration of Pam 3 CSK 4 induced brain injury in newborn animals [19].…”

Section: Discussionmentioning

confidence: 99%

Staphylococcus epidermidisBacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways

Bi¹,

Qiao²,

Bergelson³

et al. 2015

J Infect Dis.

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Background. Staphylococcus epidermidis causes late-onset sepsis in preterm infants. Staphylococcus epidermidis activates host responses in part via Toll-like receptor 2 (TLR2). Epidemiologic studies link bacteremia and neonatal brain injury, but direct evidence is lacking.Methods. Wild-type and TLR2-deficient (TLR2−/−) mice were injected intravenously with S. epidermidis at postnatal day 1 prior to measuring plasma and brain cytokine and chemokine levels, bacterial clearance, brain caspase-3 activation, white/gray matter volume, and innate transcriptome.Results. Staphylococcus epidermidis bacteremia spontaneously resolved over 24 hours without detectable bacteria in the cerebrospinal fluid (CSF). TLR2−/− mice demonstrated delayed S. epidermidis clearance from blood, spleen, and liver. Staphylococcus epidermidis increased the white blood cell count in the CSF, increased interleukin 6, interleukin 12p40, CCL2, and CXCL1 concentrations in plasma; increased the CCL2 concentration in the brain; and caused rapid (within 6 hours) TLR2-dependent brain activation of caspase-3 and TLR2-independent white matter injury.Conclusions. Staphylococcus epidermidis bacteremia, in the absence of bacterial entry into the CSF, impairs neonatal brain development. Staphylococcus epidermidis bacteremia induced both TLR2-dependent and -independent brain injury, with the latter occurring in the absence of TLR2, a condition associated with an increased bacterial burden. Our study indicates that the consequences of transient bacteremia in early life may be more severe than commonly appreciated, and our findings may inform novel approaches to reduce bacteremia-associated brain injury.

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Section: Discussionmentioning

confidence: 99%

Staphylococcus epidermidisBacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways

Bi¹,

Qiao²,

Bergelson³

et al. 2015

J Infect Dis.

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“…In the recent work, Lehnardt et al [83] and Ziegler et al [147] reported smaller infarction size in the mice lacking TLR2 receptors, yet, on the other hand, the same signaling pathway has been reported instrumental for brain neurogenesis [117]. From the experimental results, it is conceivable that in acute response to injuries activated microglial cells may play an early detrimental role that can be converted into supportive role in the later, chronic phase of the brain response to ischemic injury.…”

Section: Tlrs Response To Ischemic Injury and Neurogenesismentioning

confidence: 97%

“…More particularly, TLR2 and TLR4 can interact with endogenous alarm signals such as heat shock proteins (Hsp60 and 70), extracellular breakdown product of hyaluron lipoproteins, etc., suggesting that TLRs may be involved in the regulation of inXammatory response following brain injuries [5,47,106] and neurodegeneration [99,105]. Recent studies demonstrated that TLRs, in particular TLR2 may be an important mediator of CNS ischemic injury [83,147]. The induction of TLR2 has been also observed in the activated microglial cells in other types of brain injuries.…”

Section: Tlrs Response To Ischemic Injury and Neurogenesismentioning

confidence: 99%

Inflammation, plasticity and real-time imaging after cerebral ischemia

2009

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With an incidence of approximately 350 in 100,000, stroke is the third leading cause of death and a major cause of disability in industrialized countries. At present, although progress has been made in understanding the molecular pathways that lead to ischemic cell death, the current clinical treatments remain poorly eVective. There is mounting evidence that inXammation plays an important role in cerebral ischemia. Experimentally and clinically, brain response to ischemic injury is associated with an acute and prolonged inXammatory process characterized by the activation of resident glial cells, production of inXammatory cytokines as well as leukocyte and monocyte inWltration in the brain, events that may contribute to ischemic brain injury and aVect brain recovery and plasticity. However, whether the post-ischemic inXammatory response is deleterious or beneWcial to brain recovery is presently a matter of debate and controversies. Here, we summarize the current knowledge on the molecular mechanisms underlying post-ischemic neuronal plasticity and the potential role of inXammation in regenerative processes and functional recovery after stroke. Furthermore, because of the dynamic nature of the brain inXammatory response, we highlight the importance of the development of novel experimental approaches such as real-time imaging. Finally, we discuss the novel transgenic reporter mice models that have allowed us to visualize and to analyze the processes such as neuroinXammation and neuronal repair from the ischemic brains of live animals.

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“…What is unclear, however, is the functional significance of TLR4 upregulation under the cardiac conditions. During the past five years, evidence has emerged that clearly indicates that in addition to its role in the host immunity against invading pathogens, TLR signaling may also play a critical role in modulating cell survival and tissue injury (or repair) in "noninfectious" injury models in several organs, such as lung (68), liver (121), brain (84,144), and heart (28,118,136,149), although, to make things even more complicated, TLR signaling seems to have different roles in different injury models. Of note, all of these investigations have been carried out in mouse models where genetic modifications of target genes are readily available.…”

Section: Tlr Signaling Mediates Myocardial I/r Injurymentioning

confidence: 99%

“…The stimulation of these TLRs leads to, through their specific intracellular signaling pathways, the activation of various downstream transcription factors and the ultimate production of inflammatory cytokines in host immune cells. In addition to their pivotal role in host immune defense against invading pathogens, TLRs, demonstrated by emerging evidence from the past 5-10 years, appear capable of responding to stress and modulating inflammation and tissue damage following noninfectious insults such as hypoxia and ischemia in various tissues (107), such as the lung (68), liver (121), brain (84,144), and heart (28,36,118,136,149).…”

mentioning

confidence: 99%

Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart

Chao¹

2009

American Journal of Physiology-Heart and Circulatory Physiology

212

166

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Toll-like receptors (TLRs) represent the first line of host defense against microbial infection and play a pivotal role in both innate and adaptive immunity. TLRs recognize invading pathogens through molecular pattern recognition, transduce signals via distinct intracellular pathways involving a unique set of adaptor proteins and kinases, and ultimately lead to the activation of transcription factors and inflammatory responses. Among 10 TLRs identified in humans, at least two exist in the heart, i.e., TLR2 and TLR4. In addition to the critical role of these in mediating cardiac dysfunction in septic conditions, emerging evidence suggests that the TLRs can also recognize endogenous ligands and may play an important role in modulating cardiomyocyte survival and in ischemic myocardial injury. In animal models of ischemia-reperfusion injury or in hypoxic cardiomyocytes in vitro, the administration of a sublethal dose of lipopolysaccharide, which signals through TLR4, reduces subsequent myocardial infarction, improves cardiac functions, and attenuates cardiomyocyte apoptosis. By contrast, a systemic deficiency of TLR2, TLR4, or myeloid differentiation primary-response gene 88, an adaptor critical for all TLR signaling, except TLR3, leads to an attenuated myocardial inflammation, a smaller infarction size, a better preserved ventricular function, and a reduced ventricular remodeling after ischemic injury. These loss-of-function studies suggest that both TLRs contribute to myocardial inflammation and ischemic injury in the heart although the exact contribution of cardiac (vs. circulatory cell) TLRs remains to be defined. These recent studies demonstrate an emerging role for TLRs as a critical modulator in both cell survival and tissue injury in the heart.

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Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia

Cited by 237 publications

References 21 publications

Staphylococcus epidermidisBacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways

Staphylococcus epidermidisBacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways

Inflammation, plasticity and real-time imaging after cerebral ischemia

Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart

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