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Review
. 2025 Apr 18;26(8):3854.
doi: 10.3390/ijms26083854.

Neuroinflammation and Amyotrophic Lateral Sclerosis: Recent Advances in Anti-Inflammatory Cytokines as Therapeutic Strategies

Affiliations
Review

Neuroinflammation and Amyotrophic Lateral Sclerosis: Recent Advances in Anti-Inflammatory Cytokines as Therapeutic Strategies

Costanza Stacchiotti et al. Int J Mol Sci. .

Abstract

Neuroinflammation is an inflammatory response occurring within the central nervous system (CNS). The process is marked by the production of pro-inflammatory cytokines, chemokines, small-molecule messengers, and reactive oxygen species. Microglia and astrocytes are primarily involved in this process, while endothelial cells and infiltrating blood cells contribute to neuroinflammation when the blood-brain barrier (BBB) is damaged. Neuroinflammation is increasingly recognized as a pathological hallmark of several neurological diseases, including amyotrophic lateral sclerosis (ALS), and is closely linked to neurodegeneration, another key feature of ALS. In fact, neurodegeneration is a pathological trigger for inflammation, and neuroinflammation, in turn, contributes to motor neuron (MN) degeneration through the induction of synaptic dysfunction, neuronal death, and inhibition of neurogenesis. Importantly, resolution of acute inflammation is crucial for avoiding chronic inflammation and tissue destruction. Inflammatory processes are mediated by soluble factors known as cytokines, which are involved in both promoting and inhibiting inflammation. Cytokines with anti-inflammatory properties may exert protective roles in neuroinflammatory diseases, including ALS. In particular, interleukin (IL)-10, transforming growth factor (TGF)-β, IL-4, IL-13, and IL-9 have been shown to exert an anti-inflammatory role in the CNS. Other recently emerging immune regulatory cytokines in the CNS include IL-35, IL-25, IL-37, and IL-27. This review describes the current understanding of neuroinflammation in ALS and highlights recent advances in the role of anti-inflammatory cytokines within CNS with a particular focus on their potential therapeutic applications in ALS. Furthermore, we discuss current therapeutic strategies aimed at enhancing the anti-inflammatory response to modulate neuroinflammation in this disease.

Keywords: amyotrophic lateral sclerosis; cytokines; neuroinflammation.

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Conflict of interest statement

The authors declare that they have no financial conflicts of interest.

Figures

Figure 3
Figure 3
The role of anti-inflammatory cytokines in amyotrophic lateral sclerosis (ALS). Schematic representation of the anti-inflammatory cytokines’ effects in ALS, based on preclinical data in ALS animal models and correlative studies based on ALS patient-derived samples and their clinical information (specific references are reported). Arrows indicate the impact of cytokine on neuroinflammation and/or disease progression: sharp arrows represent exacerbation (pathogenic role), and blunt arrows represent inhibition (protective role). The protective effect of IL-10 is supported by different studies, and the protective role of IL-9 is predicted by a single study. In contrast, controversial results are reported about the roles of TGF-β, IL-4, and IL-13. Created in https://BioRender.com. Refs. [45,46,47,48,49,50,58,60,61,62,75,76,77,98,99].
Figure 1
Figure 1
Cell-autonomous and non-cell-autonomous mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Microenvironment and genetic factors might trigger motor neuron intrinsic changes (cell-autonomous mechanism) and several other cell types across the central nervous system (CNS) (non-cell autonomous mechanism). Among non-cell autonomous mechanisms, the most important is the turning of astrocytes and microglia into a pro-inflammatory state. The activation of glia cells in ALS leads to production of neurotoxic factors, which contribute to neurodegeneration, and of pro-inflammatory cytokines involved in the drastic loss of blood-brain barrier (BBB) integrity, which causes the invasion of leukocytes from blood into the CNS parenchyma. The entry of inflammatory monocytes, T lymphocytes, and B lymphocytes into the CNS enhances neuroinflammation by releasing inflammatory cytokines and reactive oxygen species to the tissue. Long and chronic neuroinflammation is linked to impaired tissue function and neurodegeneration, which further amplify inflammatory mechanisms in a pathological feedback loop.
Figure 2
Figure 2
Anti-inflammatory response counteracts the neuroinflammation. In neurodegenerative diseases, the blood-brain barrier (BBB) integrity is impaired, and invasion of leukocytes from blood into CNS parenchyma leads to neuroinflammation. However, immune cells with anti-inflammatory properties might infiltrate the CNS and produce specific anti-inflammatory cytokines contrasting neuroinflammation, and consequently neurodegeneration. In particular, the cytokines involved in this process are IL-10, TGF-β, IL-4, IL-13, IL-9, IL-35, IL-25, IL-37, IL-27, and the immune cells involved are Treg, Breg, microglia M2, macrophage M2, Th2, and Th9 cells. Cytokines may exert either driving than effector functions: IL-4 induces Th2 cells; IL-4 and TGF-β drive Th9 polarization; IL-2, TGF-β, IL-37, and IL-10 are involved in Treg expansion; IL-10 drives Breg; IL-4, IL-10, IL-13, IL-9, IL-25, IL-37, IL-27, and TGF-β polarize microglia and macrophages towards the M2 anti-inflammatory profile.

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