Microglia Responses in Acute and Chronic Neurological Diseases: What Microglia-Specific Transcriptomic Studies Taught (and did Not Teach) Us

Abstract

Over the last decade, microglia have been acknowledged to be key players in central nervous system (CNS) under both physiological and pathological conditions. They constantly survey the CNS environment and as immune cells, in pathological contexts, they provide the first host defense and orchestrate the immune response. It is well recognized that under pathological conditions microglia have both sequential and simultaneous, beneficial and detrimental effects. Cell-specific transcriptomics recently became popular in Neuroscience field allowing concurrent monitoring of the expression of numerous genes in a given cell population. Moreover, by comparing two or more conditions, these approaches permit to unbiasedly identify deregulated genes and pathways. A growing number of studies have thus investigated microglial transcriptome remodeling over the course of neuropathological conditions and highlighted the molecular diversity of microglial response to different diseases. In the present work, we restrict our review to microglia obtained directly from in vivo samples and not cell culture, and to studies using whole-genome strategies. We first critically review the different methods developed to decipher microglia transcriptome. In particular, we compare advantages and drawbacks of flow cytometry and laser microdissection to isolate pure microglia population as well as identification of deregulated microglial genes obtained via RNA sequencing (RNA-Seq) vs. microarrays approaches. Second, we summarize insights obtained from microglia transcriptomes in traumatic brain and spinal cord injuries, pain and more chronic neurological conditions including Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD) and Multiple sclerosis (MS). Transcriptomic responses of microglia in other non-neurodegenerative CNS disorders such as gliomas and sepsis are also addressed. Third, we present a comparison of the most activated pathways in each neuropathological condition using Gene ontology (GO) classification and highlight the diversity of microglia response to insults focusing on their pro- and anti-inflammatory signatures. Finally, we discuss the potential of the latest technological advances, in particular, single cell RNA-Seq to unravel the individual microglial response diversity in neuropathological contexts.

Lipid transporter Spns2 promotes microglia pro‐inflammatory activation in response to amyloid‐beta peptide

“…However, recent studies have also found that the functional effects of microglia activation are much more complex than assumed and are age and context‐dependent (Chen et al, ; Stetler et al, ). In aging or pathological conditions where chronic inflammation is predominant, microglia tend to polarize to a more destructive phenotype as exhibited in AD and other situations (Cherry et al, ; Hirbec et al, ; Parisi et al, ; Wang, Tan, Yu, & Tan, ). Thus, strategies to boost anti‐inflammatory biased phenotype while inhibiting the pro‐inflammatory phenotype may have a profound potential for effective treatment (Cherry et al, ; McGeer & McGeer, ; Wes et al, ).…”

“…Microglia, accounting for about 5–12% of all glial cells, are the first line defense of the central nervous system (Greter & Merad, ; Hirbec, Noristani, & Perrin, ; Parisi, Napoli, Pelegrin, & Volonte, ). Although more complicated functional heterogeneity is being discovered recently, microglia activation is mainly categorized into two states: the pro‐inflammatory neurotoxic state and the anti‐inflammatory neuroprotective state (Cunningham, ; Greter & Merad, ).…”

“…Although more complicated functional heterogeneity is being discovered recently, microglia activation is mainly categorized into two states: the pro‐inflammatory neurotoxic state and the anti‐inflammatory neuroprotective state (Cunningham, ; Greter & Merad, ). Pro‐inflammatory microglia are generally identified by expression of pro‐inflammatory cytokines and chemokines, such as tumor necrosis factor α (TNFα), interleukin‐6 (IL6), IL‐1β, and nitric oxide, while anti‐inflammatory‐polarized microglia identified by high expression of Arginase‐1 (Arg1), Interleukin‐4 (IL4), and CD206 (Hirbec et al, ; Parisi et al, ). Treatment with endotoxin LPS, amyloid beta peptide (Aβ), and other agents lead to pro‐inflammatory polarization, whereas treatment with anti‐inflammatory agents, such as IL4 and glatiramer acetate, result in anti‐inflammatory polarization (Cao, Karthikeyan, Dheen, Kaur, & Ling, ; Lee et al, ; McGeer & McGeer, ; Minett et al, ).…”

The microglial reaction signature revealed by RNAseq from individual mice

“…Genome-wide transcriptional profiling has also been used to decipher the transcriptional remodeling that occurs during reaction, by studying various mouse models of brain diseases, such as multiple sclerosis, Amyotrophic lateral sclerosis, and Alzheimer's disease (reviewed in Hirbec, Noristani, & Perrin, 2017). These studies provided insights into the radical modifications that reactive microglia undergo in disease states (Holtman et al, 2015), and revealed the highly dynamic behavior of microglial transcriptomes at different stages of progressive neurodegenerative diseases.…”

Advancements of the sFIDA method for oligomer‐based diagnostics of neurodegenerative diseases

“…Alzheimer's disease is a chronic neurodegenerative disorder characterized by progressive and irreversible cognitive decline . Clinically, AD is characterized by early memory deficits followed by a decline in cognitive functions .…”