Present and future of microglial pharmacology

Šimončičová, Eva; Andrade, Elisa Gonçalves de; Vecchiarelli, Haley A.; Awogbindin, Ifeoluwa O.; Delage, Charlotte; Tremblay, Marie‐Ève

doi:10.1016/j.tips.2021.11.006

Cited by 53 publications

(47 citation statements)

References 102 publications

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“…Furthermore, GFAP may also be detected in extra-neuronal tissue, which may confound results ( Hainfellner et al, 2001 ). Other markers of glial reactivity are cytokines, complement pathway mediators, purinergic receptors, CX3C motif chemokine receptor 1 (CX3CR1), colony stimulating factor 1 receptor (CSF1R), and triggering receptor expressed on myeloid cells 2 (TREM2) ( Šimončičová et al, 2021 ). However, these markers are largely non-specific for astrocytes and/or microglia, and can also originate from peripheral cells.…”

Section: Introductionmentioning

confidence: 99%

The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure

Renz‐Polster

Tremblay

Bienzle

et al. 2022

Front. Cell. Neurosci.

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Although myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has a specific and distinctive profile of clinical features, the disease remains an enigma because causal explanation of the pathobiological matrix is lacking. Several potential disease mechanisms have been identified, including immune abnormalities, inflammatory activation, mitochondrial alterations, endothelial and muscular disturbances, cardiovascular anomalies, and dysfunction of the peripheral and central nervous systems. Yet, it remains unclear whether and how these pathways may be related and orchestrated. Here we explore the hypothesis that a common denominator of the pathobiological processes in ME/CFS may be central nervous system dysfunction due to impaired or pathologically reactive neuroglia (astrocytes, microglia and oligodendrocytes). We will test this hypothesis by reviewing, in reference to the current literature, the two most salient and widely accepted features of ME/CFS, and by investigating how these might be linked to dysfunctional neuroglia. From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features – post exertional malaise and decreased cerebral blood flow – are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity.

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Section: Introductionmentioning

confidence: 99%

The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure

Renz‐Polster

Tremblay

Bienzle

et al. 2022

Front. Cell. Neurosci.

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“…Particularly, Chastain et al (2019) revealed a decreased global DNA methylation but increased acetylation of factors that upregulate inflammatory gene transcription, such as histone H3 lysine 9, which prevailed throughout adulthood. Less transcriptional repression in microglia was paralleled by an elevated GC response to a LPS challenge during adulthood and reversed by minocycline ( Chastain et al, 2019 ), a tetracycline normalizer of microglial cytokine release and phagocytosis ( Šimončičová et al, 2022 ). GC are produced by the HPA axis following exposure to physiological or biological threats and have numerous functions, largely affecting inflammatory and metabolic processes ( de Kloet et al, 2005 ; Lucassen et al, 2014 ; Picard et al, 2021 ), as well as synaptic plasticity, behavior, and memory ( McEwen and Magarinos, 2001 ).…”

Section: Suicidal Behaviors Are Associated With Increased Peripheral ...mentioning

confidence: 99%

“…Studies of human brain samples from individuals who died by suicide have revealed direct changes in microglial numbers, morphology, as well as gene and protein expression (see Supplementary Table 1 ), although their mechanisms of action remain unknown ( Suzuki et al, 2019 ; Baharikhoob and Kolla, 2020 ). Microglia are the resident immune cells of the CNS ( Šimončičová et al, 2022 ). They perform classic immune roles involving debris clearance ( Lampron et al, 2015 ), phagocytosis of infected or apoptotic cells ( Sierra et al, 2010 ; Györffy et al, 2018 ) and production of immune mediators ( Aloisi, 2001 ).…”

Section: Introductionmentioning

confidence: 99%

“…They perform classic immune roles involving debris clearance ( Lampron et al, 2015 ), phagocytosis of infected or apoptotic cells ( Sierra et al, 2010 ; Györffy et al, 2018 ) and production of immune mediators ( Aloisi, 2001 ). Their function, however, goes beyond immunity ( Šimončičová et al, 2022 ). Notably, microglia contribute to the development, maintenance, and plasticity of the CNS.…”

Section: Introductionmentioning

confidence: 99%

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Microglia as a Hub for Suicide Neuropathology: Future Investigation and Prevention Targets

Andrade

Ibáñez

Tremblay

2022

Front. Cell. Neurosci.

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Suicide is a complex public health challenge associated worldwide with one death every 40 s. Research advances in the neuropathology of suicidal behaviors (SB) have defined discrete brain changes which may hold the key to suicide prevention. Physiological differences in microglia, the resident immune cells of the brain, are present in post-mortem tissue samples of individuals who died by suicide. Furthermore, microglia are mechanistically implicated in the outcomes of important risk factors for SB, including early-life adversity, stressful life events, and psychiatric disorders. SB risk factors result in inflammatory and oxidative stress activities which could converge to microglial synaptic remodeling affecting susceptibility or resistance to SB. To push further this perspective, in this Review we summarize current areas of opportunity that could untangle the functional participation of microglia in the context of suicide. Our discussion centers around microglial state diversity in respect to morphology, gene and protein expression, as well as function, depending on various factors, namely brain region, age, and sex.

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“…Emerging knowledge on microglial heterogeneity provides an opportunity for the development of selective modulators of beneficial and/or aberrant microglial functions in a contextdependent manner. 48 Both the activated and resting microglia are greatly dynamic.…”

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confidence: 99%

NG2‐glia crosstalk with microglia in health and disease

Zuo

Zhou

et al. 2022

CNS Neurosci Ther

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Glia are non-neuronal cells, also called neuroglia. 1 Glia exist within the mammalian nervous system to provide several essential functions for neurons, such as maintaining homeostasis, support, protection, and generating myelin. 2,3 Traditionally, astrocytes, microglia, and oligodendrocytes are the three major classes of glia. In the last two decades, neuron glia antigen-2 (NG2) glial cell has been considered as the fourth type of glial cell in the central nervous system (CNS). 4 NG2-glia are also called oligodendrocyte precursor cells 5 and express NG2. [6][7][8] NG2 is a chondroitin sulphate proteoglycan 4 (CSPG4), which is also expressed on infiltrating macrophages and activated microglia in various CNS insults. 9-11 NG2, together with platelet-derived growth factor receptor alpha (PDGFRα), is a marker of NG2-glia. 12,13 NG2-glia account for 5%-10% of all cells in the adult CNS. 14 NG2-glia are extremely heterogeneous with different characteristics and functions. 15,16 NG2-glia are widely scattered in the CNS in late development and throughout adulthood. NG2-glia may differentiate into neurons or astrocytes under diverse conditions, such as at embryonic stages, and under forced expression of neurogenic factors. [17][18][19] Early postnatal NG2-glia can become multipotent neurospheres and quickly differentiate into neurons, astrocytes, and oligodendrocytes in vitro. 18 More than one-third of the protoplasmic astrocytes are differentiated from NG2-glia in ventral forebrain when NG2-Cre is prenatally triggered in NG2-glia before embryonic day 17.5. 20 A single homeodomain transcription factor Dlx2-transfects NG2-glia differentiated into GABAergic inhibitory neurons. 19 Adult NG2-glia also differentiate into neurons in the cortical gray matter. 21 The anti-epileptic epigenetic regulator valproic

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Present and future of microglial pharmacology

Cited by 53 publications

References 102 publications

The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure

The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure

Microglia as a Hub for Suicide Neuropathology: Future Investigation and Prevention Targets

NG2‐glia crosstalk with microglia in health and disease

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