Inflammasome Activation: A Keystone of Proinflammatory Response in Obstructive Sleep Apnea.

Abstract

<b>Rationale:</b> As the mechanism that links obstructive sleep apnea (OSA) with the regulation of inflammatory response is not well known, it is important to understand the inflammasome activation, mainly of NLRP3 (nucleotide-binding oligomerization domain-like receptor 3). <b>Objectives:</b> To assess the NLRP3 activity in patients with severe OSA and to identify its role in the systemic inflammatory response of patients with OSA. <b>Methods:</b> We analyzed the NLRP3 activity as well as key components of the inflammasome cascade, such as adaptor molecule apoptosis-associated speck-like protein, caspase-1, Gasdermin D, IL-1β, IL-18, and tissue factor, in monocytes and plasma from patients with severe OSA and control subjects without sleep apnea. We explored the association of the different key markers with inflammatory comorbidities. <b>Measurements and Main Results:</b> Monocytes from patients with severe OSA presented higher NLRP3 activity than those from control subjects, which directly correlated with the apnea-hypopnea index and hypoxemic indices. NLRP3 overactivity triggered inflammatory cytokines (IL-1β and IL-18) via caspase-1 and increased Gasdermin D, allowing for tissue factor to be released. <i>In vitro</i> models confirmed that monocytes increase NLRP3 signaling under intermittent hypoxia in a hypoxia-inducible factor-1α-dependent manner, and/or in combination with plasma from patients with OSA. Plasma concentrations of tissue factor were higher in patients with OSA with systemic inflammatory comorbidities than in those without them. <b>Conclusions:</b> In patients with severe OSA, NLRP3 activation might be a linking mechanism between intermittent hypoxia and other OSA-induced immediate changes with the development of systemic inflammatory response.