P2X7‐dependent, but differentially regulated release of IL‐6, CCL2, and TNF‐α in cultured mouse microglia

Shieh, Chu-Hsin; Heinrich, Annette; Serchov, Tsvetan; Calker, Dietrich van; Biber, Knut

doi:10.1002/glia.22628

Cited by 169 publications

(146 citation statements)

References 66 publications

(133 reference statements)

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“…However, the other two cytokines, TNF-α and IL-6, displayed no distinct changes. It was reported that various P2X7 receptor antagonists blocked the P2X7-dependent release of IL-6 but surprisingly had no effect on BzATP-induced release of TNF-α in cultured microglia [45]. In addition, the IL-1β levels in concentrated MVs, induced by BzATP, reduced promptly when N9 microglial cells were transfected with IL-1β shRNA lentivirus (Fig.…”

Section: Discussionmentioning

confidence: 85%

Microvesicles shed from microglia activated by the P2X7-p38 pathway are involved in neuropathic pain induced by spinal nerve ligation in rats

Jiang

et al. 2016

Purinergic Signalling

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Microglia are critical in the pathogenesis of neuropathic pain. In this study, we investigated the role of microvesicles (MVs) in neuropathic pain induced by spinal nerve ligation (SNL) in rats. First, we found that MVs shed from microglia were increased in the cerebrospinal fluid and dorsal horn of the spinal cord after SNL. Next, MVs significantly reduced paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). In addition, the P2X7-p38 pathway was related to the bleb of MVs after SNL. Interleukin (IL)-1β was found to be significantly upregulated in the package of MVs, and PWT and PWL increased following inhibition with shRNA-IL-1β. Finally, the amplitude and frequency of spontaneous excitatory postsynaptic currents increased following stimulation with MVs. Our results indicate that the P2X7-p38 pathway is closely correlated with the shedding of MVs from microglia in neuropathic pain, and MVs had a significant effect on neuropathic pain by participating in the interaction between microglia and neurons.

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Section: Discussionmentioning

confidence: 85%

Microvesicles shed from microglia activated by the P2X7-p38 pathway are involved in neuropathic pain induced by spinal nerve ligation in rats

Jiang

et al. 2016

Purinergic Signalling

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“…Indeed, genetic removal of neuronal COX-2 or EP2 antagonism can mitigate the induction of CCL2 mRNA in the brain (6,8,9) or in purified microglia (57). Another possibility is that neuronal ATP release increases CCL2 in microglia via P2X7 receptors (58). However, additional work is required to test these ideas.…”

Section: Discussionmentioning

confidence: 99%

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

Varvel

Neher

Bosch

et al. 2016

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

288

291

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The generalized seizures of status epilepticus (SE) trigger a series of molecular and cellular events that produce cognitive deficits and can culminate in the development of epilepsy. Known early events include opening of the blood-brain barrier (BBB) and astrocytosis accompanied by activation of brain microglia. Whereas circulating monocytes do not infiltrate the healthy CNS, monocytes can enter the brain in response to injury and contribute to the immune response. We examined the cellular components of innate immune inflammation in the days following SE by discriminating microglia vs. brain-infiltrating monocytes. Chemokine receptor 2 (CCR2 + ) monocytes invade the hippocampus between 1 and 3 d after SE. In contrast, only an occasional CD3 + T lymphocyte was encountered 3 d after SE. The initial cellular sources of the chemokine CCL2, a ligand for CCR2, included perivascular macrophages and microglia. The induction of the proinflammatory cytokine IL-1β was greater in FACS-isolated microglia than in brain-invading monocytes. However, Ccr2 knockout mice displayed greatly reduced monocyte recruitment into brain and reduced levels of the proinflammatory cytokine IL-1β in hippocampus after SE, which was explained by higher expression of the cytokine in circulating and brain monocytes in wild-type mice. Importantly, preventing monocyte recruitment accelerated weight regain, reduced BBB degradation, and attenuated neuronal damage. Our findings identify brain-infiltrating monocytes as a myeloid-cell subclass that contributes to neuroinflammation and morbidity after SE. Inhibiting brain invasion of CCR2 + monocytes could represent a viable method for alleviating the deleterious consequences of SE. myeloid cell heterogeneity | epileptogenesis | neuroprotection | seizure | microgliosis S tatus epilepticus (SE) is a serious medical emergency that triggers a series of cellular and molecular events that can result in the development of epilepsy, a chronic neurological disorder characterized by a persistently lowered seizure threshold (1). The early consequences of SE in rodents include a robust neuroinflammatory response, selective neuronal degeneration, and transient opening of the blood-brain barrier (BBB), leading to later cognitive decline. Although the neuroinflammatory features of SE in man are less well known, extravasation of albumin into the brain was observed for patients who died in SE (2), elevated cerebrospinal fluid levels of the cytokines IL-6, IL-8, and CXCL10 are typically found in patients with refractory SE compared with patients with other inflammatory neurologic disorders (3), and intense gliosis (both astrocytes and microglia) was observed in the temporal cortex of a patient with new-onset focal seizures that progressed to refractory SE (4). These admittedly sparse clinical findings are consistent with the much more extensive animal literature in demonstrating a florid inflammatory response of the brain to SE (5). We and others have provided evidence in animal models of epilepsy that quenching inflamma...

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“…P2X7R activation alone induced IL-6 release without the need for co-stimulatory activation through LPS. In contrast to primary cultured microglia [151], IL-6 release from the mouse microglial cell line MG-5 was stimulated via phospholipase C-linked P2YRs [156]. Another study reports increased P2X7R-dependent release of IL-6 in macrophages exposed to glioma-conditioned medium.…”

Section: Interleukin-6-type Of Cytokinesmentioning

confidence: 94%

“…Both P2X7Rs and P2Y 6 Rs appeared to be involved [146]. In microglia, ATP induced messenger RNA (mRNA) expression and release of CCL2, CCL3, and CXCL2 mainly through activation of P2X7Rs [151][152][153]. Chemokine production was mediated via both calcineurindependent nuclear factor of activated T cells (NFAT) and PKC/MAPK signaling pathways.…”

Section: Inflammatory Chemokines(c-c Motif) Ligandsmentioning

confidence: 97%

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Extracellular ATP and other nucleotides—ubiquitous triggers of intercellular messenger release

Zimmermann

2015

Purinergic Signalling

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Extracellular nucleotides, and ATP in particular, are cellular signal substances involved in the control of numerous (patho)physiological mechanisms. They provoke nucleotide receptor-mediated mechanisms in select target cells. But nucleotides can considerably expand their range of action. They function as primary messengers in intercellular communication by stimulating the release of other extracellular messenger substances. These in turn activate additional cellular mechanisms through their own receptors. While this applies also to other extracellular messengers, its omnipresence in the vertebrate organism is an outstanding feature of nucleotide signaling. Intercellular messenger substances released by nucleotides include neurotransmitters, hormones, growth factors, a considerable variety of other proteins including enzymes, numerous cytokines, lipid mediators, nitric oxide, and reactive oxygen species. Moreover, nucleotides activate or co-activate growth factor receptors. In the case of hormone release, the initially paracrine or autocrine nucleotide-mediated signal spreads through to the entire organism. The examples highlighted in this commentary suggest that acting as ubiquitous triggers of intercellular messenger release is one of the major functional roles of extracellular nucleotides. While initiation of messenger release by nucleotides has been unraveled in many contexts, it may have been overlooked in others. It can be anticipated that additional nucleotide-driven messenger functions will be uncovered with relevance for both understanding physiology and development of therapy.

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P2X7‐dependent, but differentially regulated release of IL‐6, CCL2, and TNF‐α in cultured mouse microglia

Cited by 169 publications

References 66 publications

Microvesicles shed from microglia activated by the P2X7-p38 pathway are involved in neuropathic pain induced by spinal nerve ligation in rats

Microvesicles shed from microglia activated by the P2X7-p38 pathway are involved in neuropathic pain induced by spinal nerve ligation in rats

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

Extracellular ATP and other nucleotides—ubiquitous triggers of intercellular messenger release

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