In acute experimental autoimmune encephalomyelitis, infiltrating macrophages are immune activated, whereas microglia remain immune suppressed

Vainchtein, Ilia D.; Vinet, Jonathan; Brouwer, Nieske; Brendecke, Stefanie M.; Biagini, Giuseppe; Biber, Knut; Boddeke, Hendrikus; Eggen, Bart J. L.

doi:10.1002/glia.22711

Cited by 80 publications

(66 citation statements)

References 38 publications

(40 reference statements)

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“…Monocytes contribute to the inflammatory milieu in the brain just by their infiltration, even in the absence of proinflammatory cytokine induction, whereas, in microglia, the induced expression of cytokines contributes to neuroinflammation. This finding is in contrast to the antagonist response reported in EAE models (16,63). A recent study reached similar conclusions on the role of invading monocytes after SE wherein monocytes have elevated levels of TNF-α and IL-1β when normalized to control microglia (64).…”

Section: Discussionsupporting

confidence: 56%

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.

266

269

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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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Section: Discussionsupporting

confidence: 56%

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.

266

269

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“…Microglia were acutely FACS-isolated from the brain stem as described previously using CD45 and CD11b antibodies [50]. RNA was extracted from the acutely isolated microglia and using the RNeasyMicro kit (Qiagen) according to the manufacturer’s protocol isolated using Qiagen RNeasy.…”

Section: Methodsmentioning

confidence: 99%

Telomere shortening leads to an acceleration of synucleinopathy and impaired microglia response in a genetic mouse model

Scheffold

Holtman

Dieni

et al. 2016

acta neuropathol commun

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Parkinson’s disease is one of the most common neurodegenerative disorders of the elderly and ageing hence described to be a major risk factor. Telomere shortening as a result of the inability to fully replicate the ends of linear chromosomes is one of the hallmarks of ageing. The role of telomere dysfunction in neurological diseases and the ageing brain is not clarified and there is an ongoing discussion whether telomere shortening is linked to Parkinson’s disease. Here we studied a mouse model of Parkinson’s disease (Thy-1 [A30P] α-synuclein transgenic mouse model) in the background of telomere shortening (Terc knockout mouse model). α-synuclein transgenic mice with short telomeres (αSYNtg/tg G3Terc-/-) developed an accelerated disease with significantly decreased survival. This accelerated phenotype of mice with short telomeres was characterized by a declined motor performance and an increased formation of α-synuclein aggregates. Immunohistochemical analysis and mRNA expression studies revealed that the disease end-stage brain stem microglia showed an impaired response in αSYNtg/tg G3Terc-/- microglia animals. These results provide the first experimental data that telomere shortening accelerates α-synuclein pathology that is linked to limited microglia function in the brainstem.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0364-x) contains supplementary material, which is available to authorized users.

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“…Impaired recruitment of these cells might explain why mice that harbor TAK1-deficient microglia, which fail to induce CCL2 expression, are relatively protected from EAE (58). In fact, gene expression profiling recently revealed that during EAE, resident microglia remain inert, whereas infiltrating macrophages are immune activated and express proinflammatory genes, such as IL-1β and TNF-α (57,85). Moreover, using an advanced imaging approach based on the above-mentioned CCR2-reporter mice, researchers found that monocyte-derived macrophages initiated demyelination, whereas microglia appeared dedicated to the clearance of debris (57).…”

Section: Monocyte-derived Macrophages In Pathology-associated Inflammmentioning

confidence: 97%

Macrophages: Development and Tissue Specialization

Varol

Mildner

Jung

2015

Annu. Rev. Immunol.

709

591

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Macrophages are myeloid immune cells that are strategically positioned throughout the body tissues, where they ingest and degrade dead cells, debris, and foreign material and orchestrate inflammatory processes. Here we review two major recent paradigm shifts in our understanding of tissue macrophage biology. The first is the realization that most tissue-resident macrophages are established prenatally and maintained through adulthood by longevity and self-renewal. Their generation and maintenance are thus independent from ongoing hematopoiesis, although the cells can be complemented by adult monocyte-derived macrophages. Second, aside from being immune sentinels, tissue macrophages form integral components of their host tissue. This entails their specialization in response to local environmental cues to contribute to the development and specific function of their tissue of residence. Factors that govern tissue macrophage specialization are emerging. Moreover, tissue specialization is reflected in discrete gene expression profiles of macrophages, as well as epigenetic signatures reporting actual and potential enhancer usage.

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In acute experimental autoimmune encephalomyelitis, infiltrating macrophages are immune activated, whereas microglia remain immune suppressed

Cited by 80 publications

References 38 publications

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

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

Telomere shortening leads to an acceleration of synucleinopathy and impaired microglia response in a genetic mouse model

Macrophages: Development and Tissue Specialization

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