HMGB1 and amyotrophic lateral sclerosis: Additionally, TLR4 is of increasing interest in ALS therapeutics, with another agonist of TLR4, high-mobility group box 1 (HMGB1), shown to be secreted from motoneurons and to have increased reactivity in astrocytes and microglia concurrent with ALS disease progression (Lo Coco et al., 2007; Lee et al., 2015).