title: Redox distress and genetic defects conspire in systemic autoinflammatory diseases.
abstract: 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.
authors.affiliation: Department of Paediatric Rheumatology and Immunology, University Children's Hospital Münster, Domagkstrasse 3, 48149 Münster, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Varga
authors.affiliation: Second Division of Paediatrics, G. Gaslini Institute, 16145 Genova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gattorno
authors.affiliation: Department of Paediatric Rheumatology and Immunology, University Children's Hospital Münster, Domagkstrasse 3, 48149 Münster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Foell
authors.affiliation: Cell Biology Unit, IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Rubartelli
mesh_terms: D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism*; D007375:Interleukin-1 / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress
chemical_list: D007375:Interleukin-1