Neuroinflammation, characterized by activated astrocytes and microglia, infiltrated T cells, and the subsequent production of inflammatory mediators, is a pathological hallmark of amyotrophic lateral sclerosis (ALS). Since microglia produce proinflammatory cytokines and other neurotoxic or protective molecules and astrocytes reduce their glutamate uptake, these functional changes in glial cells are considered to play important roles in neurodegeneration. However, what regulates the neuroprotective response in neuroinflammation of ALS has not been clarified. In this regard, we identify astrocyte-derived transforming growth factor-β1 (TGF-β1) as a negative regulator of neuroprotective inflammatory response by microglia and T cells. Understanding the pathomechanism of neuroinflammation of ALS leads to the development of new therapies that target glial cells and T cells.