Fig. 4

Pathogenesis and therapeutic potential of immune cells in ALS. Th17 cells produce IL-17A, activating microglia and astrocytes, leading to inflammatory responses that damage neurons in ALS. Treg cells secrete IL-10, slowing ALS progression by inhibiting neuroinflammation, regulating glial activity, promoting neuroprotection, and modulating immune responses. In astrocytes, the mitochondrial melatonin pathway inhibits pro-inflammatory factors, limiting inflammatory responses. Its reduction in ALS patients increases reactive oxygen species. The IGF1R-mTOR pathway is upregulated, inhibiting autophagy and enhancing astrocyte reactivity. In a pathogenic model, soluble APP fragments released by astrocytes activate death receptor 6 on motor neurons, triggering death signals through an NF-κB1-dependent pathway. In microglia, activation-related genes (CHIT1, CCL18, CHRNA1, GPNMB, LYZ) are upregulated in ALS. The RIPK1 pathway, activated by TNFα signaling, polarizes microglia into an inflammatory state, contributing to neurodegeneration. Myeloid cells in ALS show TREM2 receptor-mediated formation of phagocytic TDP-43 aggregates. Inhibition of STING reduces TDP-43-induced neurodegeneration by downregulating inflammatory genes through inhibition of TBK1 and IRF3 phosphorylation. C9orf72 knockout enhances myeloid cell sensitivity to STING, inducing an overactive type I IFN response. These cellular interactions and pathways contribute to neuroinflammation, neuronal damage, and disease progression in ALS. Understanding these mechanisms provides potential therapeutic targets aimed at slowing disease progression and protecting motor neurons. Figure created with BioRender.com