Cell death–mediated cytokine release and its therapeutic implications

Targeting apoptosis to treat diseases has seen tremendous success over the past decades. More recently, alternative forms of regulated cell death, including pyroptosis and necroptosis, have been described. Understanding the molecular cascades regulating both pyroptosis and necroptosis will yield even more targets to treat diseases. These lytic forms of cell death are distinct from apoptosis due to their characteristic lysis and release of cellular components that promote disease or direct a beneficial immune response. In this review, we focus on how pyroptosis and necroptosis, which release potent immune cytokines such as IL-1 and IL-18, contribute to various diseases. We also consider the important role that the executioners of these cell death pathways, GSDMD and MLKL, play in the progression of inflammatory diseases. Crosstalk between the different cell death pathways likely plays a major role physiologically. New therapeutic strategies targeting these specific molecules hold enormous potential for managing inflammatory diseases.