Therapy of autoimmune inflammation in sporadic amyotrophic lateral sclerosis: Dimethyl fumarate and H‐151 downregulate inflammatory cytokines in the cGAS‐STING pathway

Abstract

AbstractIn sporadic amyotrophic lateral sclerosis (sALS), IL‐17A‐ and granzyme‐positive cytotoxic T lymphocytes (CTL), IL‐17A‐positive mast cells, and inflammatory macrophages invade the brain and spinal cord. In some patients, the disease starts following a trauma or a severe infection. We examined cytokines and cytokine regulators over the disease course and found that, since the early stages, peripheral blood mononuclear cells (PBMC) exhibit increased expression of inflammatory cytokines IL‐12A, IFN‐γ, and TNF‐α, as well as granzymes and the transcription factors STAT3 and STAT4. In later stages, PBMCs upregulated the autoimmunity‐associated cytokines IL‐23A and IL‐17B, and the chemokines CXCL9 and CXCL10, which attract CTL and monocytes into the central nervous system. The inflammation is fueled by the downregulation of IL‐10, TGFβ, and the inhibitory T‐cell co‐receptors CTLA4, LAG3, and PD‐1, and, in vitro, by stimulation with the ligand PD‐L1. We investigated in two sALS patients the regulation of the macrophage transcriptome by dimethyl fumarate (DMF), a drug approved against multiple sclerosis and psoriasis, and the cyclic GMP‐AMP synthase/stimulator of interferon genes (cGAS/STING) pathway inhibitor H‐151. Both DMF and H‐151 downregulated the expression of granzymes and the pro‐inflammatory cytokines IL‐1β, IL‐6, IL‐15, IL‐23A, and IFN‐γ, and induced a pro‐resolution macrophage phenotype. The eicosanoid epoxyeicosatrienoic acids (EET) from arachidonic acid was anti‐inflammatory in synergy with DMF. H‐151 and DMF are thus candidate drugs targeting the inflammation and autoimmunity in sALS via modulation of the NFκB and cGAS/STING pathways.