Signal integration between IFNγ and TLR signalling pathways in macrophages

Schroder, Kate; Sweet, Matthew J.; Hume, David

doi:10.1016/j.imbio.2006.05.007

Cited by 267 publications

(244 citation statements)

References 108 publications

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“…IFN-γ is a dimerized soluble cytokine and the only member of the type II class of IFNs. It is released predominantly by leukocyte subtypes, such as NK cells, Th1 cells, and cytotoxic T lymphocytes (3,37). Exposure to IFN-γ alone resulted in different characteristics of microglia, such as higher cell numbers, in line with previously reported findings (15); however, the moderate effects on neuronal function were similar to those of LPS.…”

Section: Discussionsupporting

confidence: 82%

“…Notably, in vivo models using LPS also show inflammatory neurodegeneration and likely feature the release of IFN-γ from infiltrating leukocytes (7,(19)(20)(21). Activation of IFN-γ receptors triggers various responses in macrophages and microglia (37,51). Moreover, there is cross-talk between TLR4 and the IFN-γ receptor via autocrine and paracrine loops at various intracellular downstream cascades (37,52).…”

Section: Discussionmentioning

confidence: 99%

“…The aforementioned phenotypes avoided substantial neuronal dysfunction and damage. We next applied LPS (10 μg/mL) and IFN-γ (100 ng/mL) in combination for 72 h (11,15,37). LPS+IFN-γ strongly increased iNOS expression and NO release from microglia ( Fig.…”

Section: Lps or Ifn-γ Alone Induces Reactive Phenotypes In Microglia mentioning

confidence: 99%

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TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ

Papageorgiou

Lewen

Galow

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

158

150

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Microglia (tissue-resident macrophages) represent the main cell type of the innate immune system in the CNS; however, the mechanisms that control the activation of microglia are widely unknown. We systematically explored microglial activation and functional microglia-neuron interactions in organotypic hippocampal slice cultures, i.e., postnatal cortical tissue that lacks adaptive immunity. We applied electrophysiological recordings of local field potential and extracellular K + concentration, immunohistochemistry, design-based stereology, morphometry, Sholl analysis, and biochemical analyses. We show that chronic activation with either bacterial lipopolysaccharide through Toll-like receptor 4 (TLR4) or leukocyte cytokine IFN-γ induces reactive phenotypes in microglia associated with morphological changes, population expansion, CD11b and CD68 up-regulation, and proinflammatory cytokine (IL-1β, TNF-α, IL-6) and nitric oxide (NO) release. Notably, these reactive phenotypes only moderately alter intrinsic neuronal excitability and gamma oscillations (30-100 Hz), which emerge from precise synaptic communication of glutamatergic pyramidal cells and fast-spiking, parvalbumin-positive GABAergic interneurons, in local hippocampal networks. Short-term synaptic plasticity and extracellular potassium homeostasis during neural excitation, also reflecting astrocyte function, are unaffected. In contrast, the coactivation of TLR4 and IFN-γ receptors results in neuronal dysfunction and death, caused mainly by enhanced microglial inducible nitric oxide synthase (iNOS) expression and NO release, because iNOS inhibition is neuroprotective. Thus, activation of TLR4 in microglia in situ requires concomitant IFN-γ receptor signaling from peripheral immune cells, such as T helper type 1 and natural killer cells, to unleash neurotoxicity and inflammation-induced neurodegeneration. Our findings provide crucial mechanistic insight into the complex process of microglia activation, with relevance to several neurologic and psychiatric disorders.hippocampus | microglia | neuronal activity | slice culture | Toll-like receptor

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ

Papageorgiou

Lewen

Galow

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

158

150

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“…IFN␥ is a major inducer of TLR expression and enhancer of TLR signaling in immune cells during responses to infection and inflammation (29), and our evidence suggests that IFN␥ can also induce TLR2 and -4 expression in neurons. We also observed that levels of HSP70, a putative TLR ligand (30), were increased in association with TLR2 and -4 up-regulation and JNK activation in neurons subjected to energy deprivation.…”

Section: Discussionmentioning

confidence: 55%

Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits

Tang

Arumugam

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

703

638

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The innate immune system senses the invasion of pathogenic microorganisms and tissue injury through Toll-like receptors (TLR), a mechanism thought to be limited to immune cells. We now report that neurons express several TLRs, and that the levels of TLR2 and -4 are increased in neurons in response to IFN-␥ stimulation and energy deprivation. Neurons from both TLR2 knockout and -4 mutant mice were protected against energy deprivation-induced cell death, which was associated with decreased activation of a proapoptotic signaling cascade involving jun N-terminal kinase and the transcription factor AP-1. TLR2 and -4 expression was increased in cerebral cortical neurons in response to ischemia/reperfusion injury, and the amount of brain damage and neurological deficits caused by a stroke were significantly less in mice deficient in TLR2 or -4 compared with WT control mice. Our findings establish a proapoptotic signaling pathway for TLR2 and -4 in neurons that may render them vulnerable to ischemic death.AP-1 ͉ apoptosis ͉ innate immunity ͉ ischemic stroke ͉ microglia T oll-like receptors (TLRs) are a family of at least 11 proteins that function as key mediators of innate immunity, responding to diverse microbial products and injury-induced endogenous ligands (1). Activation of TLRs initiates signal transduction cascades that involve kinases including atypical forms of protein kinase C and the transcription factors activator protein-1 (AP-1) and NF-B, which induce the expression of genes encoding inflammation-associated molecules and cytokines (2-4). Although TLRs are expressed in leukocytes where their functions have been established, recent findings suggest they can also be expressed in nonimmune cells, including hepatocytes and muscle cells (5,6). TLRs are present in the brain, where their expression is believed to be limited to glial cells (microglia, astrocytes, and oligodentrocytes) (7,8). However, recent findings suggest that neurons may express at least some TLRs responsive to viral RNA or bacterial proteins (9, 10). Ischemic injury to the brain (stroke) is a major cause of morbidity and mortality for which effective treatments are lacking. Studies have shown that TLR2 and -4 are up-regulated in response to ischemia in the kidney and heart, suggesting these two TLRs may play important roles in ischemic tissue injury (11-13). However, neither the specific cells in which TLRs are activated in response to ischemia nor the consequences of TLR signaling for the clinical outcome of an ischemic event have been established. Here we use TLR2 and -4 mutant mice and primary neuronal cell culture and in vivo models of ischemic stroke to elucidate roles for neuronal TLR2 and -4 signaling in the pathogenesis of stroke. Results Neurons Express TLRs and Respond to IFN␥ Stimulation.Previous studies suggested that neurons do not express TLRs (14), whereas others have suggested the presence of TLR3 and -8 in neurons (10). By using multiple technologies, we found that primary mouse cortical neurons express TLR2, -3, and -4. First,...

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“…16,20,21 Often, pre-exposure of an innate immune cell to a cytokine such as IFN-γ is necessary for the cell to be able to fully activate and produce a robust immune response when exposed to a pathogen. 22,23 The cells are said to be pre-activated or 'primed' in response to stimulation with the cytokine. Typically, primed cells produce little, if any, cytokines in the absence of a contemporaneous co-stimulation by a pathogen.…”

Section: Introductionmentioning

confidence: 99%

Trained innate immunity: a salient factor in the pathogenesis of neuroimmune psychiatric disorders

2017

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Signal integration between IFNγ and TLR signalling pathways in macrophages

Cited by 267 publications

References 108 publications

TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ

TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ

Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits

Trained innate immunity: a salient factor in the pathogenesis of neuroimmune psychiatric disorders

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