Inflammation is initiated by innate immune cell activation after contact with pathogens or tissue injury. An increasing number of observations have suggested that cellular stress, in the absence of
infection or evident damage, can also induce
inflammation. Thus,
inflammation can be triggered by exogenous
pathogen-associated molecular patterns (
PAMPs) and damage-associated molecular patterns (DAMPs)-so-called classic
inflammation-or by endogenous stress resulting from tissue or cellular dysfunction. External triggers and cellular stress activate the same molecular pathways, possibly explaining why classic and stress-induced
inflammation have similar clinical manifestations. In some systemic autoinflammatory diseases (
SAIDs), inflammatory cells exhibit reduction-oxidation (redox) distress, having high levels of
reactive oxygen species (ROS), which promote proinflammatory
cytokine production and contribute to the subversion of mechanisms that self-limit
inflammation. Thus,
SAIDs can be viewed as a paradigm of stress-related
inflammation, being characterized by recurrent flares or chronic
inflammation (with no recognizable external triggers) and by a failure to downmodulate this
inflammation. Here, we review SAID pathophysiology, focusing on the major
cytokines and DAMPs, and on the key roles of redox distress. New therapeutic opportunities to tackle
SAIDs by blocking stress-induced pathways and control the response to stress in patients are also discussed.