M. Rosario Sepúlveda
João B. Relvas
Francesca Peri
Veronika E. Neubrand- 1Department of Cell Biology, Faculty of Sciences, University of Granada, Granada, Spain
- 2Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular (IBMC), University of Porto, Porto, Portugal
- 3Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
- 4Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
Editorial on the Research Topic
Cell biology of microglia
Microglia are the resident immune cells of the Central Nervous System (CNS) and play a key role during development, synapse formation, CNS plasticity and defense across life (Wolf et al., 2017). In the adult and aging brain, microglia have been identified as important players in the progression of neurodegenerative diseases with an underlying neuroinflammation. Hence, microglia are responsive to a variety of stimuli and, correspondingly, can acquire many different phenotypes (Paolicelli et al., 2022). These range from neuroprotective phenotypes, supporting the CNS, to neuroinflammatory phenotypes with fatal consequences for neurons and their environment. Although the existence of microglia has been known for more than 100 years, some of their essential functions were revealed only in recent decades. Furthermore, with technical advances in sequencing, a plethora of expression data about microglia in health and disease has lately become available (among others Gosselin et al., 2017; Friedman et al., 2018; Saunders et al., 2018; Hammond et al., 2019). However, the specific tasks of differentially regulated genes and their interactions in microglia remain largely unknown, highlighting the importance of understanding the Cell Biology of Microglia. Thus, this “Research Topic” includes six research articles and one review about intracellular mechanisms that drive microglial functions under physiological and pathological conditions.
Three of the research articles published in this Research Topic deal with microglial responses to extracellular cues and their behavior in the CNS. Lisi et al. confirm the expression of the Nerve Growth Factor (NGF) receptors, namely TrkA and p75NTR, in two human microglial cell lines. In addition, they determine the effect of NGF and its painless human recombinant mutated analog (hNGFp) on microglia activation. The authors also discuss how hNGFp appears to induce a better-defined anti-inflammatory profile compared to wild type NGF, which might improve NGF-treatment in some neuropathies. Corraliza-Gomez et al. analyze in detail the role of Apolipoprotein D (ApoD), a lipid-binding protein of the Lipocalin family, in microglial responses. ApoD, which plays an important role in CNS maintenance, increases its expression upon aging, damage or neurodegeneration. Here, the authors demonstrate that extracellular ApoD can be sensed by microglia, affecting their number and functions, and triggers cytokine signatures that are stimuli- and sex-dependent. They propose ApoD as a “priming or immune training factor”, whose exposure during life might modulate acute microglial damage responses later on. Similarly, Fernández-Arjona et al. also explore immune priming in the brain upon exposure to an immunological challenge early in life. They studied its persistence over time and the relevance of toll-like receptors (TLRs) in this process. Using a mouse model and a double stimulus paradigm design, the authors claim that such immune priming events in the brain are largely dependent on TLR4 in their experimental settings.
One of the most widely used ligands of TLR4 to induce inflammation is the lipopolysaccharide (LPS) from bacterial origin. Martín-Sierra et al. describe how LPS-stimulated microglia can induce ganglion cell death by an NO-dependent mechanism in organotypic cultures of quail embryo retina. Since phagocytic contacts between microglia and caspase-3-positive ganglion cells are increased upon LPS-treatment, the authors discuss the possibility of a cell death mechanism mediated by microglial engulfment. Working as well with retinal microglia, the following article by Wang et al. describes a new and efficient protocol to isolate primary retinal microglia from adult human post-mortem eyes. The characterization in terms of morphology, markers and response to LPS converts this method into a great tool to study the pathogenesis of inflammatory ocular diseases.
Based on the crosstalk between microglia and other glial cells, the work of Guo et al. investigate the dynamic interactions between the translocator protein (TSPO) as neuroinflammatory marker, microglia and astrocytes in a mouse model of depression. These glial interactions are examined in vivo in different hippocampal subregions by a combination of positron emission tomography (PET) technology with TSPO ligands, double-immunofluorescence and cytokine analysis.
Finally, a review article by Gabrielli et al. summarizes the current knowledge about extracellular vesicles released by microglia, including their composition, isolation and purification methods. This comprehensive review also discusses their heterogeneous properties and multifaceted effects as novel intercellular communication system.
In conclusion, this Research Topic contains several important articles for Frontiers in Cellular Neuroscience readers interested in the latest findings in microglial cell biology.
Author contributions
MRS and VEN wrote the manuscript. All authors revised, contributed to the article, and approved the submitted version.
Acknowledgments
We would like to thank the University of Granada for its financial support: PPJIA2022.29 (to VEN) and PP2022.PP.29 (to MRS).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
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References
Friedman, B. A., Srinivasan, K., Ayalon, G., Meilandt, W. J., Lin, H., Huntley, M. A., et al. (2018). Diverse brain myeloid expression profiles reveal distinct microglial activation states and aspects of alzheimer's disease not evident in mouse models. Cell Rep. 22, 832–847. doi: 10.1016/j.celrep.12066
Gosselin, D., Skola, D., Coufal, N. G., Holtman, I. R., Schlachetzki, J. C. M., Sajti, E. O'connor, C., et al. (2017). An environment-dependent transcriptional network specifies human microglia identity. Science 356, 222. doi: 10.1126./science.aal3222
Hammond, T.R., Dufort, C., Dissing-Olesen, L., Giera, S., Young, A., Wysoker, A., et al. (2019). Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the injured brain reveals complex cell-state changes. Immunity 50, 253. doi: 10.1016/j.immuni.11004
Paolicelli, R.C., Sierra, A., Stevens, B., Tremblay, M.E., Aguzzi, A., Ajami, B., et al. (2022). Microglia states and nomenclature: a field at its crossroads. Neuron 110, 3458–3483. doi: 10.1016/j.neuron.10020
Saunders, A., Macosko, E. Z., Wysoker, A., Goldman, M., Krienen, F. M., Rivera, D. e., et al. (2018). Molecular diversity and specializations among the cells of the adult mouse brain. Cell 174, 1015. doi: 10.1016/j.cell.07028
Keywords: microglia, Nerve Growth Factor (NGF), Apolipoprotein D (apoD), immune priming, toll-like receptor (TLR), lipopolysaccharide (LPS), retina, extracellular vesicles
Citation: Sepúlveda MR, Relvas JB, Peri F and Neubrand VE (2023) Editorial: Cell biology of microglia. Front. Cell. Neurosci. 17:1210124. doi: 10.3389/fncel.2023.1210124
Received: 21 April 2023; Accepted: 08 May 2023;
Published: 19 May 2023.
Edited by:
Hiroaki Wake, Nagoya University, JapanReviewed by:
Tuan Leng Tay, Boston University, United StatesCopyright © 2023 Sepúlveda, Relvas, Peri and Neubrand. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Veronika E. Neubrand, neubrand@ugr.es; M. Rosario Sepúlveda, mrsepulveda@ugr.es