Colony stimulating factor 1 receptor inhibition eliminates microglia and attenuates brain injury after intracerebral hemorrhage

Li, Minshu; Li, Zhiguo; Ren, Honglei; Jin, Wei‐Na; Wood, Kristofer; Liu, Qiang; Sheth, Kevin N; Shi, Fu‐Dong

doi:10.1177/0271678x16666551

Cited by 132 publications

(118 citation statements)

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“…Brain ischemia activates microglia that can damage neural structure or facilitate neural repair, depending on timing and context (52)(53)(54)(55). Microglia express IL-15 receptors and thus could be receptive to astrocytic IL-15.…”

Section: Discussionmentioning

confidence: 99%

Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity

Yao

et al. 2016

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

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Astrocytes are believed to bridge interactions between infiltrating lymphocytes and neurons during brain ischemia, but the mechanisms for this action are poorly understood. Here we found that interleukin-15 (IL-15) is dramatically up-regulated in astrocytes of postmortem brain tissues from patients with ischemic stroke and in a mouse model of transient focal brain ischemia. We generated a glial fibrillary acidic protein (GFAP) Infiltrating leukocytes such as lymphocytes are major effectors of postischemic brain inflammation (1-6). The phenotype and function of infiltrating lymphocytes are largely dictated by organspecific intrinsic factors during inflammatory responses (7-9), and such factors in the brain are unique in terms of cellular constituents, blood-brain barrier (10-12), and microenvironment (1-3, 7). As the most abundant cell type in the CNS, astrocytes constitute nearly 50% of the human brain's volume. Astrocytes contribute to the regulation of neural transmission, survival of neurons and other glia cells, and integrity of the blood-brain barrier. In the inflamed CNS, astrocytes engage in significant cross-talk with CNS-infiltrating immune cells by providing a major source of the proinflammatory cytokines and chemokines, thereby activating infiltrating lymphocytes. Evidence has shown that astrocytes can exert potent proinflammatory functions by producing factors including monocyte chemotactic protein-1 (MCP-1/CCL2), interleukin 1 beta (IL-1β), interleukin-6 (IL-6), etc., as their primary mode of action after CNS injury. In addition, astrocytes are considered as important nonprofessional antigen-presenting cells. Depending on the stage of brain pathology, astrocytes also possess antiinflammatory properties such as scar formation and restriction of inflammation by producing transforming growth factor-β (13,14). Recent studies have shown that the inhibition of astrocytes correlates with decreased infarct size (15,16) and that treatments capable of decreasing infarct size are often accompanied by attenuated astrocyte responses. These findings suggest a detrimental role for astrocytes after brain ischemia (15-18). However, still unknown are whether and how astrocytes shape acute CNS immune responses in the context of a postischemic brain and whether this process has any clinical significance.IL-15 belongs to a family of cytokines using the common γ-chain as a component of their receptors (19,20). IL-15 interacts specifically with the high-affinity IL-15 receptor α (IL-15Rα) and binds to IL-2/IL-15Rβ and a common γ-chain expressed by target cells (21-23). In the periphery, monocytes and dendritic cells are the main sources of 25). IL-15 maintains homeostasis and cytotoxic activities of lymphocytes that bear its receptor [i.e., natural killer (NK) and CD8 + T cells] (19,20). Some studies have demonstrated that IL-15 contributes to the immunopathology of several inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease (26,27). Despite recent studies suggesting astrocytes as a major...

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Section: Discussionmentioning

confidence: 99%

Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity

Yao

et al. 2016

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

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157

148

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“…Since many large motoneurons with high-level CSF1 expression were encircled by microglia in the spinal cords from both acute and chronic EAE mice, we presume that neuronal loss may be partly due to the action of microglia. However, Li et al (2017) reported that eliminating microglia with PLX3397 attenuated brain injury after intracerebral hemorrhage. Luo et al showed that administration of CSF1 or IL34 prevented the loss of pyramidal neurons and microgliosis in mouse hippocampus after kainic acid injection (Luo et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Increased expression of colony‐stimulating factor‐1 in mouse spinal cord with experimental autoimmune encephalomyelitis correlates with microglial activation and neuronal loss

Гущина

Pryce

Yip

et al. 2018

Glia

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Microglia contribute to pathophysiology at all stages of multiple sclerosis. Colony-stimulating factor-1 (CSF1) is crucial for microglial proliferation and activation. In this study we measured the CSF1 levels and studied its cellular expression in the mouse spinal cords with experimental autoimmune encephalomyelitis (EAE) to explore the potential contribution of CSF1 in neuronal death. ELISA data showed that CSF1 levels were significantly higher in the spinal cords with acute and chronic EAE than those of normal and adjuvant-injected mice. Immunohistochemical studies demonstrated that CSF1 was expressed in astrocytes and neurons in normal mouse spinal cord. In acute EAE, CSF1 expression was significantly increased, especially in astrocytes in peripheral white matter and large motoneurons. High density of activated microglia was observed in the gray matter where motoneurons expressed high-level CSF1 in acute EAE. Significant large motoneuron loss was seen in chronic EAE and the remaining motoneurons with high-level CSF1 were enwrapped by microglia. Viral vector mediated over-expression of CSF1 in spinal neurons induced profound proliferation and activation of microglia at the injection site and microglia enwrapped CSF1-transduced neurons and their neurites. Significant loss of large CSF1-transduced neurons was seen at 2 and 3 weeks post-viral injection. Demyelination in the CSF1-transduced areas was also significant. These results implicate that CSF1 upregulation in CNS may play an important role in the proliferation and activation of microglia in EAE, contributing to neuroinflammation and neurodegeneration. © 2018 Wiley Periodicals, Inc.

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“…In support of the hypothesis, microglial depletion has thus led to a broad range of positive and neuroprotective outcomes in distinct disease conditions by reducing neuroinflammation (Table ): ameliorating EAE (Heppner et al, ; Lassmann & Bradl, ; Nissen, Thompson, West, & Tsirka, ); enhancing remyelination in the cuprizone demyelination model (Beckmann et al, ); attenuating neurological abnormalities and brain edema in two stroke mouse models (Li, Li, et al, ); reducing mRNA levels of proinflammatory cytokines such as IL‐1β and TNF‐α induced by peripheral lipopolysaccharide injection after microglial depletion (Xie et al, ); or acute binge ethanol withdrawal with little negative effects on behavioral functions (Walter & Crews, ). In one of our previous studies, we have indicated that cranial irradiation can cause transient accumulation of microglial cells followed by persistent inflammation and pronounced expression of IL‐1β and CCL2 in the hippocampus (Han et al, ).…”

Section: Depleting Microglia In Diseases: the Friend In Need May Not mentioning

confidence: 94%

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

Han

Zhu

Zhang

et al. 2018

Glia

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Microglia are prominent immune cells in the central nervous system (CNS) and are critical players in both neurological development and homeostasis, and in neurological diseases when dysfunctional. Our previous understanding of the phenotypes and functions of microglia has been greatly extended by a dearth of recent investigations. Distinct genetically defined subsets of microglia are now recognized to perform their own independent functions in specific conditions. The molecular profiling of single microglial cells indicates extensively heterogeneous reactions in different neurological disorders, resulting in multiple potentials for crosstalk with other kinds of CNS cells such as astrocytes and neurons. In settings of neurological diseases it could thus be prudent to establish effective cell‐based therapies by targeting entire microglial networks. Notably, activated microglial depletion through genetic targeting or pharmacological therapies within a suitable time window can stimulate replenishment of the CNS niche with new microglia. Additionally, enforced repopulation through provision of replacement cells also represents a potential means of exchanging dysfunctional with functional microglia. In each setting the newly repopulated microglia might have the potential to resolve ongoing neuroinflammation. In this review, we aim to summarize the most recent knowledge of microglia and to highlight microglial depletion and subsequent repopulation as a promising cell replacement therapy. Although glial cell replacement therapy is still in its infancy and future translational studies are still required, the approach is scientifically sound and provides new optimism for managing the neurotoxicity and neuroinflammation induced by activated microglia.

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Colony stimulating factor 1 receptor inhibition eliminates microglia and attenuates brain injury after intracerebral hemorrhage

Cited by 132 publications

References 54 publications

Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity

Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity

Increased expression of colony‐stimulating factor‐1 in mouse spinal cord with experimental autoimmune encephalomyelitis correlates with microglial activation and neuronal loss

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

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