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  • Review Article
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Redox distress and genetic defects conspire in systemic autoinflammatory diseases

Nature Reviews Rheumatology volume 11, pages 670–680 (2015)Cite this article

Subjects

Key Points

  • Despite several advances, the pathogenesis of systemic autoinflammatory diseases (SAIDs) is only partially understood, and how mutations in causative genes lead to increased IL-1β secretion is unclear in many of these conditions

  • Circulating monocytes from patients with SAIDs are in a state of stress, possibly owing to the presence of mutated proteins

  • Levels of damage-associated molecular patterns (DAMPs) are increased in patients with SAIDs, and these concur with cytokines to generate amplifying loops that sustain inflammation

  • We propose that stress lowers the threshold for activation of immune cells in SAIDs, promoting oxidative stress with consequent loss of control of proinflammatory and anti-inflammatory cytokine production

  • Individual resistance to stress can explain the variable severity of the clinical manifestations in patients with SAIDs sharing the same mutation, and suggests that stress pathways could be a therapeutic target in these 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.

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Figure 1: Lower threshold of activation and inability to self-limit inflammation in SAID inflammatory cells.
Figure 2: Stress links gene defects and proinflammatory and anti-inflammatory cytokine dysregulation in SAIDs.
Figure 3: Treatment options to prevent self-perpetuating inflammatory loops in SAIDs.

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Acknowledgements

The authors' work is supported in part by the Italian Ministry of Health (M.G., A.R.), by Telethon, Italy (grant n. GGP14144; M.G., A.R.) and by Associazione Italiana per la Ricerca sul Cancro (grant n. IG15434; A.R.).

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Authors and Affiliations

  1. Department of Paediatric Rheumatology and Immunology, University Children's Hospital Münster, Domagkstrasse 3, Münster, 48149, Germany

    Georg Varga & Dirk Foell

  2. Second Division of Paediatrics, G. Gaslini Institute, Genova, 16145, Italy

    Marco Gattorno

  3. Cell Biology Unit, IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Largo Rosanna Benzi 10, Genoa, 16132, Italy

    Anna Rubartelli

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  1. Georg Varga
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  2. Marco Gattorno
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Contributions

G.V. and A.R. reviewed and edited the manuscript before submission. All authors researched data for the article, made substantial contributions to discussion of content and wrote the manuscript.

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Correspondence to Anna Rubartelli.

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Competing interests

M.G. has received lecture fees and institutional unrestricted grants from SoBi and Novartis; D.F. has received lecture fees from Chugai, Novartis, Pfizer, Roche and SoBi; A.R. has received lecture fees from SoBi and Novartis; G.V. declares no competing interests.

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Varga, G., Gattorno, M., Foell, D. et al. Redox distress and genetic defects conspire in systemic autoinflammatory diseases. Nat Rev Rheumatol 11, 670–680 (2015). https://doi.org/10.1038/nrrheum.2015.105

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