Selective proliferative response of microglia to alternative polarization signals

Pepe, Giovanna; Maglie, Marcella De; Minoli, Lucia; Villa, Alessandro; Maggi, Adriana; Vegeto, Elisabetta

doi:10.1186/s12974-017-1011-6

Cited by 39 publications

(27 citation statements)

References 42 publications

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“…Alike, we here observed an increase in anti-inflammatory markers on softer substrates, while we did not detect an alteration in pro-inflammatory markers. Additionally, converging with previous studies connecting anti-inflammatory states with microglial proliferation (Pepe et al, 2017;Vay et al, 2018), we found soft substrates to increase cell proliferation significantly.…”

Section: Discussionsupporting

confidence: 89%

Substrate Elasticity Exerts Functional Effects on Primary Microglia

Blaschke

Demir

König

et al. 2020

Front. Cell. Neurosci.

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Microglia-the brain's primary immune cells-exert a tightly regulated cascade of proand anti-inflammatory effects upon brain pathology, either promoting regeneration or neurodegeneration. Therefore, harnessing microglia emerges as a potential therapeutic concept in neurological research. Recent studies suggest that-besides being affected by chemokines and cytokines-various cell entities in the brain relevantly respond to the mechanical properties of their microenvironment. For example, we lately reported considerable effects of elasticity on neural stem cells, regarding quiescence and differentiation potential. However, the effects of elasticity on microglia remain to be explored.Under the hypothesis that the elasticity of the microenvironment affects key characteristics and functions of microglia, we established an in vitro model of primary rat microglia grown in a polydimethylsiloxane (PDMS) elastomer-based cell culture system. This way, we simulated the brain's physiological elasticity range and compared it to supraphysiological stiffer PDMS controls. We assessed functional parameters of microglia under "resting" conditions, as well as when polarized towards a pro-inflammatory phenotype (M1) by lipopolysaccharide (LPS), or an anti-inflammatory phenotype (M2) by interleukin-4 (IL-4). Microglia viability was unimpaired on soft substrates, but we found various significant effects with a more than twofold increase in microglia proliferation on soft substrate elasticities mimicking the brain (relative to PDMS controls). Furthermore, soft substrates promoted the expression of the activation marker vimentin in microglia. Moreover, the M2-marker CD206 was upregulated in parallel to an increase in the secretion of Insulin-Like Growth Factor-1 (IGF-1). The upregulation of CD206 was abolished by blockage of stretch-dependent chloride channels. Our data suggest that the cultivation of microglia on substrates of brain-like elasticity promotes a basic anti-inflammatory activation state via stretch-dependent chloride

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Section: Discussionsupporting

confidence: 89%

Substrate Elasticity Exerts Functional Effects on Primary Microglia

Blaschke

Demir

König

et al. 2020

Front. Cell. Neurosci.

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“…However, microglial depletion by CSF1R inhibitor resulted in dramatically increased the number of neutrophils and augmented the astrocytic production of inflammatory mediators in brain tissues, which eventually exacerbated neurological deficits and brain infarction after ischemic stroke [25,26]. Furthermore, previous studies have also been reported that CSF1 signaling influenced the phenotype of mononuclear phagocytes, and triggered microglial polarization toward an M2-like phenotype (immunosuppressive), with increased production of anti-inflammatory cytokine IL-10 [60,61]. All these studies indicated that CSF1 activated proliferation and differentiation of microglia, thus reducing neuroinflammation and playing a neuroprotective role, while the correlation between CSF1 and HIE has not been reported.…”

Section: Discussionmentioning

confidence: 99%

Rh-CSF1 attenuates neuroinflammation via the CSF1R/PLCG2/PKCε pathway in a rat model of neonatal HIE

Xiao

Liu

Doycheva

et al. 2020

J Neuroinflammation

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Background: Hypoxic-ischemic encephalopathy (HIE) is a life-threatening cerebrovascular disease. Neuroinflammation plays an important role in the pathogenesis of HIE, in which microglia are key cellular mediators in the regulation of neuroinflammatory processes. Colony-stimulating factor 1 (CSF1), a specific endogenous ligand of CSF1 receptor (CSF1R), is crucial in microglial growth, differentiation, and proliferation. Recent studies showed that the activation of CSF1R with CSF1 exerted anti-inflammatory effects in a variety of nervous system diseases. This study aimed to investigate the anti-inflammatory effects of recombinant human CSF1 (rh-CSF1) and the underlying mechanisms in a rat model of HIE. Methods: A total of 202 10-day old Sprague Dawley rat pups were used. HI was induced by the right common carotid artery ligation with subsequent exposure of 2.5-h hypoxia. At 1 h and 24 h after HI induction, exogenous rh-CSF1 was administered intranasally. To explore the underlying mechanism, CSF1R inhibitor, BLZ945, and phospholipase C-gamma 2 (PLCG2) inhibitor, U73122, were injected intraperitoneally at 1 h before HI induction, respectively. Brain infarct area, brain water content, neurobehavioral tests, western blot, and immunofluorescence staining were performed. Results: The expressions of endogenous CSF1, CSF1R, PLCG2, protein kinase C epsilon type (PKCε), and cAMP response element-binding protein (CREB) were gradually increased after HIE. Rh-CSF1 significantly improved the neurological deficits at 48 h and 4 weeks after HI, which was accompanied by a reduction in the brain infarct area, brain edema, brain atrophy, and neuroinflammation. Moreover, activation of CSF1R by rh-CSF1 significantly increased the expressions of p-PLCG2, p-PKCε, and p-CREB, but inhibited the activation of neutrophil infiltration, and downregulated the expressions of IL-1β and TNF-α. Inhibition of CSF1R and PLCG2 abolished these neuroprotective effects of rh-CSF1 after HI.

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“…The increase in NOX-2 activity is relevant for excitotoxic damage and the inflammatory process. It has been suggested that it contributes, along with various cytokines, to the function impairment and secondary damage orchestrated by microglia [71, 72]. Persistent inflammation can promote secondary tissue injury through excess production of proinflammatory factors, such as TNF-α, IL-1β, and IL-6.…”

Section: Discussionmentioning

confidence: 99%

Role of NADPH oxidase-2 in the progression of the inflammatory response secondary to striatum excitotoxic damage

Hernández-Espinosa

Massieu

Montiel

et al. 2019

J Neuroinflammation

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Background During excitotoxic damage, neuronal death results from the increase in intracellular calcium, the induction of oxidative stress, and a subsequent inflammatory response. NADPH oxidases (NOX) are relevant sources of reactive oxygen species (ROS) during excitotoxic damage. NADPH oxidase-2 (NOX-2) has been particularly related to neuronal damage and death, as well as to the resolution of the subsequent inflammatory response. As ROS are crucial components of the regulation of inflammatory response, in this work, we evaluated the role of NOX-2 in the progression of inflammation resulting from glutamate-induced excitotoxic damage of the striatum in an in vivo model. Methods The striata of wild-type C57BL/6 J and NOX-2 KO mice (gp91 Cybbtm1Din/J ) were stereotactically injected with monosodium glutamate either alone or in combination with IL-4 or IL-10. The damage was evaluated in histological sections stained with cresyl violet and Fluoro-Jade B. The enzymatic activity of caspase-3 and NOX were also measured. Additionally, the cytokine profile was identified by ELISA and motor activity was verified by the tests of the cylinder, the adhesive tape removal, and the inverted grid. Results Our results show a neuroprotective effect in mice with a genetic inhibition of NOX-2, which is partially due to a differential response to excitotoxic damage, characterized by the production of anti-inflammatory cytokines. In NOX-2 KO animals, the excitotoxic condition increased the production of interleukin-4, which could contribute to the production of interleukin-10 that decreased neuronal apoptotic death and the magnitude of striatal injury. Treatment with interleukin-4 and interleukin-10 protected from excitotoxic damage in wild-type animals. Conclusions The release of proinflammatory cytokines during the excitotoxic event promotes an additional apoptotic death of neurons that survived the initial damage. During the subsequent inflammatory response to excitotoxic damage, ROS generated by NOX-2 play a decisive role in the extension of the lesion and consequently in the severity of the functional compromise, probably by regulating the anti-inflammatory cytokines production. Electronic supplementary material The online version of this article (10.1186/s12974-019-1478-4) contains supplementary material, which is available to authorized users.

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Selective proliferative response of microglia to alternative polarization signals

Cited by 39 publications

References 42 publications

Substrate Elasticity Exerts Functional Effects on Primary Microglia

Substrate Elasticity Exerts Functional Effects on Primary Microglia

Rh-CSF1 attenuates neuroinflammation via the CSF1R/PLCG2/PKCε pathway in a rat model of neonatal HIE

Role of NADPH oxidase-2 in the progression of the inflammatory response secondary to striatum excitotoxic damage

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