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

In 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 , a nd 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. Amyotrophic lateral sclerosis (ALS) is a paralyzing disease affecting both young and old subjects. About 5–10% of ALS cases are genetically inherited (familial ALS), while 90–95% of cases develop “sporadic” ALS (sALS) without a positive family history. Neuropathological studies demonstrate that sALS is an inflammatory disease involving an attack by cytotoxic T cells, mast cells, and inflammatory macrophages on the neurons in the brain and spinal cord. Peripheral blood mononuclear cells (PBMC) of sALS patients show increasing “autoimmune” (i.e. self-directed) messages against autologous DNA and microbial molecules. We treated sALS patients’ immune cells with the drug dimethyl fumarate (DMF), which is an approved drug against the autoimmune disease multiple sclerosis, and the molecule H-151, which blocks autoimmu