Palmitoyl‐protein thioesterase‐1 (PPT1) deficiency causes infantile neuronal ceroid lipofuscinosis (INCL), a devastating childhood neurodegenerative storage disorder. We previously reported that neuronal apoptosis in INCL is mediated by endoplasmic reticulum‐stress. ER‐stress disrupts Ca2+‐homeostasis and stimulates the expression of Ca2+‐binding proteins. We report here that in the PPT1‐deficient human and mouse brain the levels of S100B, a Ca2+‐binding protein, and its receptor, RAGE (receptor for advanced glycation end‐products) are elevated. We further demonstrate that activation of RAGE signaling in astroglial cells mediates pro‐inflammatory cytokine production, which is inhibited by SiRNA‐mediated suppression of RAGE expression. We propose that RAGE signaling contributes to neuroinflammation in INCL.