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Cell stress increases ATP release in NLRP3 inflammasome-mediated autoinflammatory
diseases, resulting in cytokine imbalance
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Carta S
; Penco F
; Lavieri R
; Martini A
; Dinarello CA
; Gattorno M
; Rubartelli A
Proc Natl Acad Sci U S A
2015[Mar]; 112
(9
): 2835-40
PMID25730877
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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? 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? (fivefold) and IL-18 (10-fold) when
stimulated with 1,000-fold less LPS than that required for full IL-1? secretion
in control subjects. Unexpectedly, IL-1? secretion is increased 10-fold,
indicating that inflammatory episodes in CAPS may not be entirely a result of
IL-1? but may also involve IL-1?. In CAPS monocytes, LPS induces the
externalization of copious amounts of ATP (10-fold), which drive IL-1?, IL-18,
and IL-1? 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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