Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 9, Pages 2835-2840Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1424741112
Keywords
interleukin 1 family; primary monocytes; reactive oxygen species; redox stress
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Funding
- Telethon, Italy [GGP14144]
- NIH [AI-15614, AR-45584]
- Italian Ministry of Health [GR-2010-2309622]
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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-1 beta 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-1 beta (fivefold) and IL-18 (10-fold) when stimulated with 1,000-fold less LPS than that required for full IL-1 beta secretion in control subjects. Unexpectedly, IL-1 alpha secretion is increased 10-fold, indicating that inflammatory episodes in CAPS may not be entirely a result of IL-1 beta but may also involve IL-1 alpha. In CAPS monocytes, LPS induces the externalization of copious amounts of ATP (10-fold), which drive IL-1 beta, IL-18, and IL-1 alpha 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.
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