Deciphering the heterogeneity of myeloid cells during neuroinflammation in the single‐cell era

Abstract

Multiple sclerosis (MS) is a disabling neuroinflammatory disease, which is little understood and lacks a sufficient therapeutic regimen. Myeloid cells have repeatedly shown to play a pivotal role in the disease progression. During homeostasis, only the CNS‐resident microglia and CNS‐associated macrophages are present in the CNS. Neuroinflammation causes peripheral immune cells to infiltrate the CNS contributing to disease progression and neurological sequelae. The differential involvement of the diverse peripheral and resident myeloid cell subsets to the disease pathogenesis and outcome are highly debated and difficult to assess. However, novel technological advances (new mouse models, single‐cell RNA‐Sequencing, and CYTOF) have improved the depth of immune profiling, which allows the characterization of distinct myeloid subsets. This review provides an overview of current knowledge on the phenotypes and roles of these different myeloid subsets in neuroinflammatory disease and their therapeutic relevance.

The P2X7 Receptor in Microglial Cells Modulates the Endolysosomal Axis, Autophagy, and Phagocytosis

“…Of particular relevance here is the increased expression of degradative lysosomal enzymes such as dipeptidyl peptidase, tripeptidyl peptidase, and Cathepsin D (CatD) in microglial cells as compared to macrophages (Majumdar et al, 2007). Also important in this regard are differences between microglial cells from inflamed CNS and those recruited from bloodderived monocytes; the substantial differences recently identified between these cell types implies their response to the P2X 7 receptor could well differ (Lapenna et al, 2018;Borst and Prinz, 2020;Yu et al, 2020). While the relative paucity of data from microglial cells on how the P2X 7 receptor alters clearance means that some of the information presented in this review has been obtained from macrophages, the reader should be aware that application of results from macrophages to microglial cells has limitations.…”

Protein Expression of the Microglial Marker Tmem119 Decreases in Association With Morphological Changes and Location in a Mouse Model of Traumatic Brain Injury

“…Less invasive means to distinguish resident microglia from infiltrated macrophages rely on cytofluorimetry by assessing the marker CD45, which is expressed at low levels in resident cells ( Martin et al, 2017 ; Rangaraju et al, 2018 ), or more recently, on the use of single-cell RNA sequencing. This latter technique has helped identify the specific transcriptional fingerprints of selective brain myeloid populations ( Borst and Prinz, 2020 ; Olah et al, 2020 ; Rajan et al, 2020 ; Hsiao et al, 2021 ). However, both cytofluorimetry and single-cell transcriptomics need tissue disintegration, thus, failing to keep enough spatial information, which is certainly a key aspect to be considered when studying focal brain injuries.…”

Spatial transcriptomic brain imaging reveals the effects of immunomodulation therapy upon specific regional brain cells in mouse dementia model

“…Signature transcriptomes between reactive and homeostatic microglia (and also astrocytes) was also surveyed for their conjoint expression between both states. Homeostatic transcriptomes were designated to exclude the signature of reactive transcriptomes and vice versa, referring to the literature reports by Prinz et al [106][107][108][109][110][111][112] , and Kim et al 105 , so that Sall1 and Hexb took the role of counting the number of microglia as each microglia express these genes constitutively while assuming that these transcriptomes did not increase in quantity per microglia when reactive 105,111 . As spatial transcriptomic imaging using Visium yielded linear (semi)quantitative (due to log1p transformation for further processing using Seurat 4.0)) metric, no fractional presentation was adopted to disclose that homeostatic microglia were increased in quantity of signature per spot in 5xFAD mice compared with wild type or P301L mice.…”