Cell stress increases ATP release in NLRP3 inflammasome-mediated autoinflammatory diseases, resulting in cytokine imbalance.
Cell stress is implicated in triggering bouts of systemic inflammation in patients with autoinflammatory disorders. Blood monocytes from patients affected by NLRP3-mediated cryopyrin-associated periodic syndromes (CAPS) release greater amounts of IL-1β than monocytes from unaffected subjects. Here we show that stress lowers the threshold of activation; blood monocytes from CAPS patients maintain the high levels of secreted IL-1β (fivefold) and IL-18 (10-fold) when stimulated with 1,000-fold less LPS than that required for full IL-1β secretion in control subjects. Unexpectedly, IL-1α secretion is increased 10-fold, indicating that inflammatory episodes in CAPS may not be entirely a result of IL-1β but may also involve IL-1α. In CAPS monocytes, LPS induces the externalization of copious amounts of ATP (10-fold), which drive IL-1β, IL-18, and IL-1α release via activation of the P2X purinoceptor 7. This enhanced ATP release appears to be the link between cell stress and increased cytokine secretion in CAPS. In the later phase after LPS stimulation, CAPS monocytes undergo oxidative stress, which impairs production of the anti-inflammatory IL-1 receptor antagonist (IL-1Ra). Remarkably, IL-1Ra secretion is fully restored by treatment with antioxidants. In two patients with the same NLRP3 mutation, but different disease severity, monocytes from the mildly affected patient exhibited more efficient redox response, lower ATP secretion, and more balanced cytokine production. Thus, the robustness of the individual antioxidant response increases the tolerance to stress and reduces the negative effect of the disease. Pharmacologic block of P2X purinoceptor 7 and improved stress tolerance may represent novel treatment strategies in stress-associated inflammatory diseases.
Cell Biology Unit, IRCCS Azienda Ospedaliera Universitaria San Martino-IST, 16132 Genova, Italy;
Sonia
S
Carta
Pediatrics II Unit, G. Gaslini Institute, 16147 Genova, Italy; Department of Pediatrics, University of Genoa, 16145 Genova, Italy;
Federica
F
Penco
Cell Biology Unit, IRCCS Azienda Ospedaliera Universitaria San Martino-IST, 16132 Genova, Italy;
Rosa
R
Lavieri
Pediatrics II Unit, G. Gaslini Institute, 16147 Genova, Italy; Department of Pediatrics, University of Genoa, 16145 Genova, Italy;
Alberto
A
Martini
Department of Medicine, University of Colorado Denver, Aurora, CO 80045; and Department of Medicine, Radboud University Medical Centre, Nijmegen HB6500, The Netherlands cdinarello@me.com anna.rubartelli@hsanmartino.it.
Charles Anthony
CA
Dinarello
Pediatrics II Unit, G. Gaslini Institute, 16147 Genova, Italy;
Marco
M
Gattorno
Cell Biology Unit, IRCCS Azienda Ospedaliera Universitaria San Martino-IST, 16132 Genova, Italy; cdinarello@me.com anna.rubartelli@hsanmartino.it.
Anna
A
Rubartelli
D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D056587:Cryopyrin-Associated Periodic Syndromes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007223:Infant; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010084:Oxidation-Reduction / Q000187:drug effects; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D013312:Stress, Physiological
D002352:Carrier Proteins; D016207:Cytokines; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate
interleukin 1 family; primary monocytes; reactive oxygen species; redox stress