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. 2017 Apr 4;8:345. doi: 10.3389/fimmu.2017.00345

Figure 2.

Figure 2

A model for stress-mediated cytokine secretion in cryopyrin-associated periodic syndromes (CAPS) monocytes. (A) In healthy monocytes, toll-like receptor (TLR) stimulation induces the production of low amounts of reactive oxygen species (ROS), rapidly neutralized by the antioxidant response. The ROS-induced ATP release is low, resulting in processing and secretion of little amounts of IL-1β through secretory lysosomes. The anti-inflammatory cytokine IL-1Ra is produced, contributing to switch off the inflammatory response. (B) In CAPS monocytes, small doses of TLR agonists induce a strong increase of ROS resulting in release of large amounts of endogenous ATP and IL-1β. The state of stress may trigger pyroptotic secretion of IL-1β through activation of caspase-11/4 that cleaves gasdermin D (GSDMD) generating a toxin-like N-terminal peptide that forms pores on the plasma membrane. Mature IL-1β, cleaved by the NLRP3 inflammasome, will be released through gasdermin D-formed pores. Later, failure of antioxidant response and mitochondria dysfunctions lead to severe oxidative stress, with impaired production of IL-1Ra. NLRP3*, mutated NLRP3.