Defects in Mitochondrial Clearance Predispose Human Monocytes to Interleukin-1β Hypersecretion

Abstract

Background: Periodic fever syndromes are caused by deregulation of interleukin-1␤ release. Results: Defective autophagy leads to accumulation of damaged mitochondria in monocytes. Conclusion: Mitochondrial components in the cytosol cause priming of monocytes for interleukin-1␤ release. Significance: The molecular mechanism behind deregulated cytokine secretion provides new clues for intervention.Most hereditary periodic fever syndromes are mediated by deregulated IL-1␤ secretion. The generation of mature IL-1␤ requires two signals: one that induces synthesis of inflammasome components and substrates and a second that activates inflammasomes. The mechanisms that mediate autoinflammation in mevalonate kinase deficiency, a periodic fever disease characterized by a block in isoprenoid biosynthesis, are poorly understood. In studying the effects of isoprenoid shortage on IL-1 ␤ generation, we identified a new inflammasome activation signal that originates from defects in autophagy. We find that hypersecretion of IL-1␤ and IL-18 requires reactive oxygen species and is associated with an oxidized redox status of monocytes but not lymphocytes. IL-1␤ hypersecretion by monocytes involves decreased mitochondrial stability, release of mitochondrial content into the cytosol and attenuated autophagosomal degradation. Defective autophagy, as established by ATG7 knockdown, results in prolonged cytosolic retention of damaged mitochondria and increased IL-1␤ secretion. Finally, activation of autophagy in healthy but not mevalonate kinase deficiency patient cells reduces IL-1␤ secretion. Together, these results indicate that defective autophagy can prime monocytes for mitochondria-mediated NLRP3 inflammasome activation, thereby contributing to hypersecretion of IL-1␤ in mevalonate kinase deficiency.Periodic fever syndromes are characterized by inflammation that occurs in the absence of apparent infection or high titer autoantibodies (1, 2). In most periodic fever syndromes, the generalized inflammation is driven by IL-1␤ generated through proteolytic cleavage by the NLRP3 inflammasome. An additional feature associated with inflammation is the production of reactive oxygen species (ROS) 3 (3, 4). During infection, ROS produced by NADPH-oxidase subunits at the plasma membrane are beneficial because ROS in phagosomes contribute to the killing of intracellular pathogens (5). In several inflammatory diseases, including periodic fever syndromes, ROS levels are increased in the cytosol and contribute to pathology (6). ROS play roles as intracellular second messengers and have immediate effects on the intracellular redox status. In TNF receptor 1-associated periodic syndrome (TRAPS), for example, mitochondria-derived ROS facilitate inflammatory cytokine production (7). Mitochondria are believed to be the main source of ROS in several autoinflammatory disorders (8).ROS are normally generated within mitochondria as byproducts of oxidative phosphorylation, but when liberated in the cytosol ROS can facilitate activation of the NLRP3 inflammas...

Molecular mechanisms regulating NLRP3 inflammasome activation

“…129 Recent studies have identified a key role of autophagy in activation of the NLRP3 inflammasome. [130][131][132][133] Autophagy acts as a negative regulator of NLRP3 inflammasome activation through various mechanisms, including direct inhibition of NLRP3 inflammasome activation by removing sources of endogenous NLRP3 inflammasome agonists, such as damaged mitochondria and mitochondrial DNA, 62,69,132 suppression of IL-1b secretion by targeting pro-IL-1b for lysosomal degradation, 134 and selective degradation of inflammasome components, such as NLRP3 and ASC. 131,135 More detailed information on the negative regulation of the NLRP3 inflammasome, including the roles of microRNAs and autophagy, has been detailed in recent reviews.…”

Unprenylated RhoA Contributes to IL-1β Hypersecretion in Mevalonate Kinase Deficiency Model through Stimulation of Rac1 Activity

“…Rac1 and RhoA can be reciprocally regulated (22,23), suggesting the possibility that deficiency in RhoA prenylation may cause Rac1 activation and thereby drive IL-1␤-driven autoinflammation. We tested this hypothesis in a culture-based MKD model, where THP-1 monocytic cells were pretreated 24 to 48 h with 10 M simvastatin (13,15). Simvastatin targets HMG-CoA reductase, the rate-limiting enzyme in the cholesterol synthesis cascade.…”

“…Inhibition of Rac1 in THP-1 monocyte cultures leads to normalization of IL-1␤ levels (14). Yet there are a number of other biochemical hallmarks of MKD, including altered autophagy, mitochondrial potential, and morphology and redox balance that cannot be explained by aberrant activity of Rac1 alone (15). Henneman et al (16) reported that RhoA, normally prenylated, activity was increased in MKD patient-derived fibroblasts, which however do not display the autoinflammation phenotype.…”

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

“…MKD patients exhibit periodic fever syndrome and hypersecretion of IL-1 and IgD. Interestingly, improved efficiency of mevalonate kinase folding in MKD does not attenuate clinical symptoms, suggesting that protein misfolding/ stablility may be altered, potentially priming the NLRP3 inflammasome by inducing expression of pro-IL-1 [31]. The ER stress in MKD has been linked to defective mitophagy and neutralization of mtROS in MKD reduces inflammasome activity.…”

“…Interestingly, MKD cells were resistant to reduction in IL-1 production by the autophagy activator rapamycin, suggesting that the isoprenoid MKD defect may activate the inflammasome through a mechanisms not regulated by autophagy [31]. Genetic defects in the proteasome itself have been recently found to cause autoinflammatory disease.…”