Differential roles of microglia and monocytes in the inflamed central nervous system

Yamasaki, Ryo; Lu, Haiyan; Butovsky, Oleg; Ohno, Nobuhiko; Rietsch, Anna; Cialic, Ron; Wu, Pauline M.; Doykan, Camille; Lin, Jessica; Cotleur, Anne C.; Kidd, Grahame J.; Zorlu, Musab M.; Sun, Nathan; Hu, Weiwei; Liu, Li Ping; Lee, Jar Chi; Taylor, Sarah E.; Uehlein, Lindsey; Dixon, Debra; Gu, Jin; Floruta, Crina M.; Zhu, Min; Charo, Israel F.; Weiner, Howard L.; Ransohoff, Richard M.

doi:10.1084/jem.20132477

Cited by 684 publications

(644 citation statements)

References 45 publications

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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: 54%

“…monocytes from brain-resident microglia (16,49). Indeed, histological examination of saline solution-treated Ccr2 +/rfp animals revealed virtually no parenchymal CCR2-RFP expression in brainresident microglia (Fig.…”

Section: Discussionmentioning

confidence: 92%

“…In the experimental autoimmune encephalomyelitis (EAE) rodent model of multiple sclerosis, gene-expression profiles indicate that infiltrating monocytes are highly inflammatory compared with microglia. Moreover, invading monocytes induce axonal damage by initiating demyelination, whereas microglia clear debris (16). By contrast, monocytes provide neuroprotection and promote healing after damage to retinal ganglion cells (17) and facilitate recovery after spinal cord injury (18).…”

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confidence: 99%

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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.

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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: 54%

Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 99%

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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.

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266

274

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“…p21 is a p53 target gene, implicated in cell cycle arrest, tumor suppression and used as a marker of cellular senescence (Serrano et al ., 1997). Interestingly, genes previously reported in activated microglia such as Egr‐1, CCl3, Chi3l3, Chi3l4, and Lyz1 (McMahon & Monroe, 1996; Chang et al ., 2001; Babcock et al ., 2003; Friedle et al ., 2011) and in proliferation such as Fos, Jun, and Mapk8 (Yamasaki et al ., 2014) were found to be mildly but significantly downregulated in G4 mTerc −/− microglia.…”

Section: Discussionmentioning

confidence: 89%

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

et al. 2015

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SummaryMicroglia are a proliferative population of resident brain macrophages that under physiological conditions self‐renew independent of hematopoiesis. Microglia are innate immune cells actively surveying the brain and are the earliest responders to injury. During aging, microglia elicit an enhanced innate immune response also referred to as ‘priming’. To date, it remains unknown whether telomere shortening affects the proliferative capacity and induces priming of microglia. We addressed this issue using early (first‐generation G1 mTerc−/−)‐ and late‐generation (third‐generation G3 and G4 mTerc−/−) telomerase‐deficient mice, which carry a homozygous deletion for the telomerase RNA component gene (mTerc). Late‐generation mTerc−/− microglia show telomere shortening and decreased proliferation efficiency. Under physiological conditions, gene expression and functionality of G3 mTerc−/− microglia are comparable with microglia derived from G1 mTerc−/− mice despite changes in morphology. However, after intraperitoneal injection of bacterial lipopolysaccharide (LPS), G3 mTerc−/− microglia mice show an enhanced pro‐inflammatory response. Nevertheless, this enhanced inflammatory response was not accompanied by an increased expression of genes known to be associated with age‐associated microglia priming. The increased inflammatory response in microglia correlates closely with increased peripheral inflammation, a loss of blood–brain barrier integrity, and infiltration of immune cells in the brain parenchyma in this mouse model of telomere shortening.

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“…Mouse microglial cells are recruited to Ab plaques (17), where they are believed to uptake plaques by phagocytosis (18,19) and release inflammatory cytokines (20), however it has been suggested that human microglia do not appear to significantly influence plaque clearance in AD brains (21). In addition to resident microglia, peripheral monocytes infiltrate the brain parenchyma under pathological condition, and several studies have indicated that infiltrating monocytes have distinct functional characteristics compared to resident microglia (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

The human-specificCASP4gene product contributes to Alzheimer-related synaptic and behavioural deficits

Kajiwara¹,

McKenzie

Dorr

et al. 2016

Hum. Mol. Genet.

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Recent studies have indicated that innate immune signalling molecules are involved in late-onset Alzheimer's disease (LOAD) risk. Amyloid beta (Ab) accumulates in AD brain, and has been proposed to act as a trigger of innate immune responses. Caspase-4 is an important part of the innate immune response. We recently characterized transgenic mice carrying human CASP4, and observed that the mice manifested profound innate immune responses to lipopolysaccharide (LPS). Since these inflammatory processes are important in the aetiology of AD, we have now analysed the correlation of expression of caspase-4 in human brain with AD risk genes, and studied caspase-4 effects on AD-related phenotypes in APPswe/PS1deltaE9 (APP/PS1) mice. We observed that the expression of caspase-4 was strongly correlated with AD risk genes including TYROBP, TREM2, CR1, PSEN1, MS4A4A and MS4A6A in LOAD brains. Caspase-4 expression was upregulated in CASP4/APP/PS1 mice in a region-specific manner, including hippocampus and prefrontal cortex. In APP/PS1 mice, caspase-4 expression led to impairments in the reversal phase of a Barnes maze task and in hippocampal synaptic plasticity, without affecting soluble or aggregated Ab levels. Caspase-4 was expressed predominantly in microglial cells, and in the presence of CASP4, more microglia were clustered around amyloid plaques. Furthermore, our data indicated that caspase-4 modulates microglial cells in a manner that increases proinflammatory processes. We propose that microglial caspase-4 expression contributes to the cognitive impairments in AD, and that further study of caspase-4 will enhance our understanding of AD pathogenesis and may lead to novel therapeutic targets in AD.

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Differential roles of microglia and monocytes in the inflamed central nervous system

Abstract: Phagocytic monocyte-derived macrophages associate with the nodes of Ranvier and initiate demyelination while microglia clear debris and display a suppressed metabolic gene signature in EAE.

Cited by 684 publications

References 45 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

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

The human-specificCASP4gene product contributes to Alzheimer-related synaptic and behavioural deficits

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