Neuroinflammation seems to play a pivotal role in various chronic neurodegenerative diseases, characterized also by the pathogenetic accumulation of specific protein aggregates. Several of these proteins have been shown to be substrates of transglutaminases, calcium-dependent enzymes that catalyze protein crosslinking reactions. Recently, it has been demonstrated that transglutaminase 2 (TG2), a member of the transglutaminase enzymes family, may also be involved in molecular mechanisms underlying inflammation. In the central nervous system, microglia and astrocytes are the cell types mainly involved in the inflammatory process. The topic suggested is focused on the increases of TG2 protein expression and enzyme activity that occur in neuronal and in non neuronal cells, such as glial, microglial and monocyte cells in response to inflammatory stimuli.