Cien Años de Microglía: Milestones in a Century of Microglial Research

Sierra, Amanda; Paolicelli, Rosa Chiara; Kettenmann, Helmut

doi:10.1016/j.tins.2019.09.004

Cited by 152 publications

(145 citation statements)

References 117 publications

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“…We recently applied a CSF-1R inhibitor targeting CSF-1R-dependent microglia in another hereditary CNS disease model. Mice carrying point mutations in the PLP1 gene that have previously been found in multiple sclerosis patients [ 20 , 23 , 72 ] were successfully treated with PLX3397 which attenuated neuroinflammation-related neural damage [ 24 ], adding to the growing evidence that microglial reactions play important roles in a plethora of CNS disorders comprising genetically mediated diseases [ 26 , 65 ].…”

Section: Introductionmentioning

confidence: 99%

Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice

Berve

West²,

Martini

et al. 2020

J Neuroinflammation

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Background The neuronal ceroid lipofuscinoses (CLN diseases) are fatal lysosomal storage diseases causing neurodegeneration in the CNS. We have previously shown that neuroinflammation comprising innate and adaptive immune reactions drives axonal damage and neuron loss in the CNS of palmitoyl protein thioesterase 1-deficient (Ppt1−/−) mice, a model of the infantile form of the diseases (CLN1). Therefore, we here explore whether pharmacological targeting of innate immune cells modifies disease outcome in CLN1 mice. Methods We applied treatment with PLX3397 (150 ppm in the chow), a potent inhibitor of the colony stimulating factor-1 receptor (CSF-1R) to target innate immune cells in CLN1 mice. Experimental long-term treatment was non-invasively monitored by longitudinal optical coherence tomography and rotarod analysis, as well as analysis of visual acuity, myoclonic jerks, and survival. Treatment effects regarding neuroinflammation, neural damage, and neurodegeneration were subsequently analyzed by histology and immunohistochemistry. Results We show that PLX3397 treatment attenuates neuroinflammation in CLN1 mice by depleting pro-inflammatory microglia/macrophages. This leads to a reduction of T lymphocyte recruitment, an amelioration of axon damage and neuron loss in the retinotectal system, as well as reduced thinning of the inner retina and total brain atrophy. Accordingly, long-term treatment with the inhibitor also ameliorates clinical outcomes in CLN1 mice, such as impaired motor coordination, visual acuity, and myoclonic jerks. However, we detected a sex- and region-biased efficacy of CSF-1R inhibition, with male microglia/macrophages showing higher responsiveness toward depletion, especially in the gray matter of the CNS. This results in a better treatment outcome in male Ppt1−/− mice regarding some histopathological and clinical readouts and reflects heterogeneity of innate immune reactions in the diseased CNS. Conclusions Our results demonstrate a detrimental impact of innate immune reactions in the CNS of CLN1 mice. These findings provide insights into CLN pathogenesis and may guide in the design of immunomodulatory treatment strategies.

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Section: Introductionmentioning

confidence: 99%

Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice

Berve

West²,

Martini

et al. 2020

J Neuroinflammation

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“…Recent studies have also applied optogenetics to manipulate glial activity, particularly astrocytes, in the normal and diseased brain 21,22,23,43 . Despite the increasing interest in microglial function in the CNS, optogenetic tools have not been used to study microglia due to the lack of effective viral tools for microglial research 44,45 . To this end, we first generated CX3CR creER/+ : R26 LSL-ReaChR/+ transgenic mice, which inducibly express ReaChR in CNS microglia, and validated its function.…”

Section: Discussionmentioning

confidence: 99%

Optogenetic activation of spinal microglia triggers chronic pain in mice

Liu

Umpierre

et al. 2020

Preprint

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Spinal microglia are highly responsive to peripheral nerve injury and are known to be a key player in neuropathic pain. However, there has not been any direct evidence showing selective microglial activation in vivo is sufficient to induce chronic pain. Here we used optogenetic approaches in microglia to address this question employing CX3CR1creER/+: R26LSL-ReaChR/+ transgenic mice, in which red-activated channelrhodopsin (ReaChR) is inducibly and specifically expressed in microglia. We found that activation of ReaChR by red light in spinal microglia evoked reliable inward currents and membrane depolarization. In vivo optogenetic activation of microglial ReaChR in the spinal cord triggered chronic pain hypersensitivity lasting for 5-7 days. In addition, activation of microglial ReaChR upregulated neuronal c-fos expression and enhanced C-fiber responses. Mechanistically, ReaChR activation led to a reactive microglial phenotype with increased IL-1β production. IL-1 receptor antagonist was able to reverse the pain hypersensitivity and neuronal hyperactivity induced by microglial ReaChR activation. Therefore, our work demonstrates that optogenetic activation of spinal microglia is sufficient to trigger chronic pain phenotypes by increasing neuronal activity via IL-1 signaling.

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“…59 Microglia act as innate immune sentinels of the brain parenchyma, and perform classical macrophage functions such as coordinating phagocytic disposal of debris and inflammatory cytokine production. 60 However, microglia have additional functions in neurogenesis, blood-brain barrier (BBB) permeability, vasculogenesis, myelination, synapse pruning, and neuronal connectivity. 60 Microglial morphology transforms during activation, going from a highly branched or "ramified" state during homeostasis to an "ameboid" activated state in response to infection, injury, protein aggregate deposition, and other overt activators of innate immune signaling.…”

Section: The Role Of Microglia In Homeostasis and Admentioning

confidence: 99%

“…60 However, microglia have additional functions in neurogenesis, blood-brain barrier (BBB) permeability, vasculogenesis, myelination, synapse pruning, and neuronal connectivity. 60 Microglial morphology transforms during activation, going from a highly branched or "ramified" state during homeostasis to an "ameboid" activated state in response to infection, injury, protein aggregate deposition, and other overt activators of innate immune signaling. 61 Microglia express a repertoire of cell surface receptors known as PRRs that enable them to sense and respond to a diverse array of immunostimulatory triggers in the CNS.…”

Section: The Role Of Microglia In Homeostasis and Admentioning

confidence: 99%

The role of innate immunity in Alzheimer's disease

Ennerfelt

Lukens

2020

Immunological Reviews

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The amyloid hypothesis has dominated Alzheimer's disease (AD) research for almost 30 years. This hypothesis hinges on the predominant clinical role of the amyloid beta (Aβ) peptide in propagating neurofibrillary tangles (NFTs) and eventual cognitive impairment in AD. Recent research in the AD field has identified the brain‐resident macrophages, known as microglia, and their receptors as integral regulators of both the initiation and propagation of inflammation, Aβ accumulation, neuronal loss, and memory decline in AD. Emerging studies have also begun to reveal critical roles for distinct innate immune pathways in AD pathogenesis, which has led to great interest in harnessing the innate immune response as a therapeutic strategy to treat AD. In this review, we will highlight recent advancements in our understanding of innate immunity and inflammation in AD onset and progression. Additionally, there has been mounting evidence suggesting pivotal contributions of environmental factors and lifestyle choices in AD pathogenesis. Therefore, we will also discuss recent findings, suggesting that many of these AD risk factors influence AD progression via modulation of microglia and immune responses.

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Cien Años de Microglía: Milestones in a Century of Microglial Research

Cited by 152 publications

References 117 publications

Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice

Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice

Optogenetic activation of spinal microglia triggers chronic pain in mice

The role of innate immunity in Alzheimer's disease

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