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Review
. 2023 Jul 8;24(14):11251.
doi: 10.3390/ijms241411251.

Looking to the Future of the Role of Macrophages and Extracellular Vesicles in Neuroinflammation in ALS

Elisabetta Carata  1 , Marco Muci  1 , Simona Di Giulio  1 , Stefania Mariano  1 , Elisa Panzarini  1
Affiliations
Review

Looking to the Future of the Role of Macrophages and Extracellular Vesicles in Neuroinflammation in ALS

Elisabetta Carata et al. Int J Mol Sci. .

Abstract

Neuroinflammation is a common pathological feature of amyotrophic lateral sclerosis (ALS). Although scientific evidence to date does not allow defining neuroinflammation as an ALS trigger, its role in exacerbating motor neuron (MNs) degeneration and disease progression is attracting research interest. Activated CNS (Central Nervous System) glial cells, proinflammatory peripheral and infiltrated T lymphocytes and monocytes/macrophages, as well as the immunoreactive molecules they release, represent the active players for the role of immune dysregulation enhancing neuroinflammation. The crosstalk between the peripheral and CNS immune cells significantly correlates with the survival of ALS patients since the modification of peripheral macrophages can downregulate inflammation at the periphery along the nerves and in the CNS. As putative vehicles for misfolded protein and inflammatory mediators between cells, extracellular vesicles (EVs) have also drawn particular attention in the field of ALS. Both CNS and peripheral immune cells release EVs, which are able to modulate the behavior of neighboring recipient cells; unfortunately, the mechanisms involved in EVs-mediated communication in neuroinflammation remain unclear. This review aims to synthesize the current literature regarding EV-mediated cell-to-cell communication in the brain under ALS, with a particular point of view on the role of peripheral macrophages in responding to inflammation to understand the biological process and exploit it for ALS management.

Keywords: amyotrophic lateral sclerosis; extracellular vesicles; macrophages; macrophages polarization; motor neuron–glial cells–macrophages communication; neuroinflammation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A) Transmission electron microscope image of EVs released by mSOD1 NSC-34 motoneuron-like cells. (B) A schematic presentation of the structure of EVs. A lipid bilayer encapsulates the water-soluble cargo. Structural lipids include ceramide, sphingolipids, and phospholipids; EVs membrane proteins include major histocompatibility complex I and II (MHC I-II), cluster of differentiation, receptors, and integrins. EVs contain a variety of regulatory molecules, including DNAs, messenger RNAs (mRNA), noncoding RNAs (ncRNA), proteins, and metabolites.
Figure 2
Figure 2
Probable axis of macrophages–extracellular vesicles in amyotrophic lateral sclerosis. Motor neurons (MNs) release into CNS extracellular vesicles (EVs) containing inflammatory molecules able to elicit activation of microglia that release anti- and pro-inflammatory cytokines modulating amyotrophic lateral signs. EVs pass the blood–brain barrier and reach peripheral macrophages secreting cytokines with a dual role: anti-inflammatory cytokines mediating MNs protection and ensuring muscle functionality; pro-inflammatory cytokines contributing to MNs degeneration and muscle atrophy. Peripheral macrophages can reach SNC and contribute to resolving or exacerbating neuroinflammation. Figure was drawn using the web-based tool BioRender (Toronto, Canada).
See this image and copyright information in PMC

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This research received no external funding.