Microglia: Brain cells on the move

Smolders, Sophie; Kessels, Sofie; Vangansewinkel, Tim; Rigo, Jean-Michel; Legendre, Pascal; Brône, Bert

doi:10.1016/j.pneurobio.2019.04.001

Cited by 92 publications

(90 citation statements)

References 352 publications

(505 reference statements)

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“…These contrasting effects may reflect the pleiotropic functions of HuR or be an indirect effect of HuR KO on other gene targets (Abdelmohsen & Gorospe, 2010). We previously showed that HuR positively regulates other ECM modulators in MG, including MMP12, ITGB3, Adamts1, and Thrombospondin 1 which also contribute to microglial and/or glioma cell migration/invasion (Ferrer, Moura Neto, & Mentlein, 2018;Smolders et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Deletion of the RNA regulator HuR in tumor‐associated microglia and macrophages stimulates anti‐tumor immunity and attenuates glioma growth

Wang

Leavenworth

Hjelmeland

et al. 2019

Glia

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Glioblastoma is a malignant brain tumor that portends a poor prognosis. Its resilience, in part, is related to a remarkable capacity for manipulating the microenvironment to promote its growth and survival. Microglia/macrophages are prime targets, being drawn into the tumor and stimulated to produce factors that support tumor growth and evasion from the immune system. Here we show that the RNA regulator, HuR, plays a key role in the tumor‐promoting response of microglia/macrophages. Knockout (KO) of HuR led to reduced tumor growth and proliferation associated with prolonged survival in a murine model of glioblastoma. Analysis of tumor composition by flow cytometry showed that tumor‐associated macrophages (TAMs) were decreased, more polarized toward an M1‐like phenotype, and had reduced PD‐L1 expression. There was an overall increase in infiltrating CD4+ cells, including Th1 and cytotoxic effector cells, and a concomitant reduction in tumor‐associated polymorphonuclear myeloid‐derived suppressor cells. Molecular and cellular analyses of HuR KO TAMs and cultured microglia showed changes in migration, chemoattraction, and chemokine/cytokine profiles that provide potential mechanisms for the altered tumor microenvironment and reduced tumor growth in HuR KO mice. In summary, HuR is a key modulator of pro‐glioma responses by microglia/macrophages through the molecular regulation of chemokines, cytokines, and other factors. Our findings underscore the relevance of HuR as a therapeutic target in glioblastoma.

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Section: Discussionmentioning

confidence: 99%

Deletion of the RNA regulator HuR in tumor‐associated microglia and macrophages stimulates anti‐tumor immunity and attenuates glioma growth

Wang

Leavenworth

Hjelmeland

et al. 2019

Glia

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“…Although the past years witnessed rapid progression in microglial research, microglia have largely been regarded as a holistic entity or homogenously polarized population in both CNS developmental and diseased conditions so far. Nevertheless, microglial researchers, including us, have begun to investigate various aspects of microglial heterogeneities [12][13][14][15][16][17][18][19]. In awake of such increasing attentions on this phenomenon, this review focuses on recent advances in examining the diversity of microglial phenotypes across different compartments of the adult brain as well as the potentially causative intrinsic and extrinsic factors.…”

Section: Introductionmentioning

confidence: 99%

Microglial regional heterogeneity and its role in the brain

2019

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Microglia have been recently shown to manifest a very interesting phenotypical heterogeneity across different regions in the mammalian central nervous system (CNS). However, the underlying mechanism and functional meaning of this phenomenon are currently unclear. Baseline diversities of adult microglia in their cell number, cellular and subcellular structures, molecular signature as well as relevant functions have been discovered. But recent transcriptomic studies using bulk RNAseq and single-cell RNAseq have produced conflicting results on region-specific signatures of microglia. It is highly speculative whether such spatial heterogeneity contributes to varying sensitivities of individual microglia to the same physiological and pathological signals in different CNS regions, and hence underlie their functional relevance for CNS disease development. This review aims to thoroughly summarize up-to-date knowledge on this specific topic and provide some insights on the potential underlying mechanisms, starting from microgliogenesis. Understanding regional heterogeneity of microglia in the context of their diverse neighboring neurons and other glia may provide an important clue for future development of innovative therapies for neuropsychiatric disorders.

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“…Microglia derive from mesodermal progenitors that arise from the yolk sac and colonize the neuroepithelium by day E9.5 [3]. Microglia are a self-renewing, distinct population of tissue macrophages and play fundamental roles in development and homeostasis of the CNS [4]. In the last decade, there has been a tremendous progress in understanding different aspects of microglia biology and this helped to contextualize and analyze their responses under pathological conditions [5].…”

Section: Introductionmentioning

confidence: 99%

MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia

Plastira

Bernhart

Joshi

et al. 2020

J Neuroinflammation

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Background: In the extracellular environment, lysophosphatidic acid (LPA) species are generated via autotaxin (ATX)-mediated hydrolysis of lysophospholipid precursors. Members of the LPA family are potent lipid mediators transmitting signals via six different G protein-coupled LPA receptors (LPAR1-6). The LPA signaling axis is indispensable for brain development and function of the nervous system; however, during damage of the central nervous system, LPA levels can increase and aberrant signaling events counteract brain function. Here, we investigated regulation of the ATX/LPA/LPAR axis in response to lipopolysaccharide-induced systemic inflammation in mice and potential neurotoxic polarization programs in LPA-activated primary murine microglia. Methods: In vivo, LPAR1-6 expression was established by qPCR in whole murine brain homogenates and in FACSsorted microglia. ELISAs were used to quantitate LPA concentrations in the brain and cyto-/chemokine secretion from primary microglia in vitro. Transcription factor phosphorylation was analyzed by immunoblotting, and plasma membrane markers were analyzed by flow cytometry. We used MAPK inhibitors to study signal integration by the JNK, p38, and ERK1/2 branches in response to LPA-mediated activation of primary microglia. Results: Under acute and chronic inflammatory conditions, we observed a significant increase in LPA concentrations and differential regulation of LPAR, ATX (encoded by ENPP2), and cytosolic phospholipase A2 (encoded by PLA2G4A) gene expression in the brain and FACS-sorted microglia. During pathway analyses in vitro, the use of specific MAPK antagonists (SP600125, SB203580, and PD98059) revealed that JNK and p38 inhibition most efficiently attenuated LPA-induced phosphorylation of proinflammatory transcription factors (STAT1 and-3, p65, and c-Jun) and secretion of IL-6 and TNFα. All three inhibitors decreased LPA-mediated secretion of IL-1β, CXCL10, CXCL2, and CCL5. The plasma membrane marker CD40 was solely inhibited by SP600125 while all three inhibitors affected expression of CD86 and CD206. All MAPK antagonists reduced intracellular COX-2 and Arg1 as well as ROS and NO formation, and neurotoxicity of microglia-conditioned media.

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Microglia: Brain cells on the move

Cited by 92 publications

References 352 publications

Deletion of the RNA regulator HuR in tumor‐associated microglia and macrophages stimulates anti‐tumor immunity and attenuates glioma growth

Deletion of the RNA regulator HuR in tumor‐associated microglia and macrophages stimulates anti‐tumor immunity and attenuates glioma growth

Microglial regional heterogeneity and its role in the brain

MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia

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