Microglial Physiology and Pathophysiology: Insights from Genome-wide Transcriptional Profiling

Crotti, Andrea; Ransohoff, Richard M.

doi:10.1016/j.immuni.2016.02.013

Cited by 283 publications

(252 citation statements)

References 84 publications

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“…In this context, the instrumental role of microglia for brain development and functionality is unquestionable [21]. Whether microglia activation is also instrumental for pathogen elimination, or whether mononuclear cells from the periphery do this job, remains unclear.…”

Section: Discussionmentioning

confidence: 99%

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Balancing the immune response in the brain: IL-10 and its regulation

Lobo-Silva

Carriche

Castro

et al. 2016

J Neuroinflammation

316

199

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BackgroundThe inflammatory response is critical to fight insults, such as pathogen invasion or tissue damage, but if not resolved often becomes detrimental to the host. A growing body of evidence places non-resolved inflammation at the core of various pathologies, from cancer to neurodegenerative diseases. It is therefore not surprising that the immune system has evolved several regulatory mechanisms to achieve maximum protection in the absence of pathology.Main bodyThe production of the anti-inflammatory cytokine interleukin (IL)-10 is one of the most important mechanisms evolved by many immune cells to counteract damage driven by excessive inflammation. Innate immune cells of the central nervous system, notably microglia, are no exception and produce IL-10 downstream of pattern recognition receptors activation. However, whereas the molecular mechanisms regulating IL-10 expression by innate and acquired immune cells of the periphery have been extensively addressed, our knowledge on the modulation of IL-10 expression by central nervous cells is much scattered. This review addresses the current understanding on the molecular mechanisms regulating IL-10 expression by innate immune cells of the brain and the implications of IL-10 modulation in neurodegenerative disorders.ConclusionThe regulation of IL-10 production by central nervous cells remains a challenging field. Answering the many remaining outstanding questions will contribute to the design of targeted approaches aiming at controlling deleterious inflammation in the brain.

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Section: Discussionmentioning

confidence: 99%

“…Microglia are the resident macrophages of the brain and the only CNS cells of haematopoietic origin [21]. Microglia arise from the yolk sac-derived primitive macrophage population and migrate to the brain early in development, completing their maturation in the forming CNS [22, 23].…”

Section: Global Concepts On the Immune Response In The Cnsmentioning

confidence: 99%

Balancing the immune response in the brain: IL-10 and its regulation

Lobo-Silva

Carriche

Castro

et al. 2016

J Neuroinflammation

316

199

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“…Microglial cells play critical roles in immune surveillance and host defense by acting as the prime resident innate‐immune cells in the central nervous system (CNS; Perry & Holmes, 2014; Salter & Beggs, 2014). Under normal conditions, microglial cells not only provide surveillance of the CNS environment but also respond to danger signals (Crotti & Ransohoff, 2016; Perry & Teeling, 2013). Activated microglial cells undergo morphological transformation (increase in the size of cell bodies and thickness of proximal processes and decreased ramification of distal branches; Plastira et al., 2016; Walker et al., 2014) and secrete pro‐inflammatory cytokines, leading to self‐perpetuating damage to the neurons, also known as the classically activated M1 phenotype.…”

Section: Introductionmentioning

confidence: 99%

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

et al. 2018

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SummaryMicroglia‐mediated neuroinflammation plays a dual role in various brain diseases due to distinct microglial phenotypes, including deleterious M1 and neuroprotective M2. There is growing evidence that the peroxisome proliferator‐activated receptor γ (PPARγ) agonist rosiglitazone prevents lipopolysaccharide (LPS)‐induced microglial activation. Here, we observed that antagonizing PPARγ promoted LPS‐stimulated changes in polarization from the M1 to the M2 phenotype in primary microglia. PPARγ antagonist T0070907 increased the expression of M2 markers, including CD206, IL‐4, IGF‐1, TGF‐β1, TGF‐β2, TGF‐β3, G‐CSF, and GM‐CSF, and reduced the expression of M1 markers, such as CD86, Cox‐2, iNOS, IL‐1β, IL‐6, TNF‐α, IFN‐γ, and CCL2, thereby inhibiting NFκB–IKKβ activation. Moreover, antagonizing PPARγ promoted microglial autophagy, as indicated by the downregulation of P62 and the upregulation of Beclin1, Atg5, and LC3‐II/LC3‐I, thereby enhancing the formation of autophagosomes and their degradation by lysosomes in microglia. Furthermore, we found that an increase in LKB1–STRAD–MO25 complex formation enhances autophagy. The LKB1 inhibitor radicicol or knocking down LKB1 prevented autophagy improvement and the M1‐to‐M2 phenotype shift by T0070907. Simultaneously, we found that knocking down PPARγ in BV2 microglial cells also activated LKB1–AMPK signaling and inhibited NFκB–IKKβ activation, which are similar to the effects of antagonizing PPARγ. Taken together, our findings demonstrate that antagonizing PPARγ promotes the M1‐to‐M2 phenotypic shift in LPS‐induced microglia, which might be due to improved autophagy via the activation of the LKB1–AMPK signaling pathway.

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“…Furthermore, it is difficult to discriminate between M1 or each M2 subtype in vitro , and even more so in vivo . Recent technical advancements, including the fluorescent analysis of activation markers, cell sorting, and single-cell RNA-seq analysis, have helped to define microglia-specific genes compared to those specific to macrophages and other glia (Butovsky et al, 2014; Crotti and Ransohoff, 2016). However, M1/M2 phenotypes of microglia do not precisely match the microglial classification based on a transcriptomic analysis such as RNA-seq (Yamasaki et al, 2014).…”

Section: Introduction: Diversity Of Microglial Phenotypes and Diseasementioning

confidence: 99%

Pharmacological Modulation of Functional Phenotypes of Microglia in Neurodegenerative Diseases

Song

Suk

2017

Front. Aging Neurosci.

144

112

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Microglia are the resident innate immune cells of the central nervous system that mediate brain homeostasis maintenance. Microglia-mediated neuroinflammation is a hallmark shared by various neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Numerous studies have shown microglial activation phenotypes to be heterogeneous; however, these microglial phenotypes can largely be categorized as being either M1 or M2 type. Although the specific classification of M1 and M2 functionally polarized microglia remains a topic for debate, the use of functional modulators of microglial phenotypes as potential therapeutic approaches for the treatment of neurodegenerative diseases has garnered considerable attention. This review discusses M1 and M2 microglial phenotypes and their relevance in neurodegenerative disease models, as described in recent literature. The modulation of microglial polarization toward the M2 phenotype may lead to development of future therapeutic and preventive strategies for neuroinflammatory and neurodegenerative diseases. Thus, we focus on recent studies of microglial polarization modulators, with a particular emphasis on the small-molecule compounds and their intracellular target proteins.

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Microglial Physiology and Pathophysiology: Insights from Genome-wide Transcriptional Profiling

Cited by 283 publications

References 84 publications

Balancing the immune response in the brain: IL-10 and its regulation

Balancing the immune response in the brain: IL-10 and its regulation

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

Pharmacological Modulation of Functional Phenotypes of Microglia in Neurodegenerative Diseases

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