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. 2023 Jul 26;14:1223096. doi: 10.3389/fimmu.2023.1223096

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Copyright © 2023 Calafatti, Cocozza, Limatola and Garofalo

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.

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Microglial dialogue with non-neuronal cells in Amyotrophic Lateral Sclerosis. Microglia (M) induce motor neuron (MN) degeneration in ALS by secreting reactive oxygen species (ROS) and pro-inflammatory cytokines, such as Interleukin 1 beta (IL-1β), Interleukin 6 (IL-6) and Tumor Necrosis Factor (TNF-α). Microglial crosstalk with non-neuronal cells shapes their phenotype, either skewing it towards a pro-inflammatory (red arrows) on anti-inflammatory (green arrows) phenotype. Microglial-derived pro-inflammatory cytokines Interleukin 1 alpha (IL-1α), TNFα and complement component C1q induce pro-inflammatory astrocytes (A). Conversely, activated astrocytes promote inflammatory microglial responses via Transforming Growth Factor β (TGF-β) and TNF‐α. Reactive astrocytes also exert toxic effects on MNs by secreting inflammatory mediators such as Prostaglandin E2 (PgE2), Leukotriene B4 (LBT4) and nitric oxide (NO). Chemokine ligand 2 receptor (CCR2)-expressing macrophages (M1) are recruited by the Chemokine Ligand 2 (CCL2) released by microglia. ROS pathway in classically activated macrophages induces microglial activation. Regulatory T cells (Treg) suppress microglial toxicity as well as other immune cells (not shown) through Interleukin 4 (IL-4), Interleukin 10 (IL-10) and TGF-β. Notably, TGF-β effect on microglia is context- and cell-dependent. Microglia-CD8+ Effector T cell (Teff) crosstalk drives neuroinflammation in ALS, with Interferon gamma (IFN-γ) secreted by the latter likely playing a role. Infiltrated Natural Killer Cells (NKC) instruct microglia towards an inflammatory profile by the release of IFN-γ. Additionally, NKCs are neurotoxic to MNs via NKG2D - NKG2D ligand (MULT1) interaction.