Defective mitochondrial fission augments NLRP3 inflammasome activation

Abstract

Despite the fact that deregulated NLRP3 inflammasome activation contributes to the pathogenesis of chronic inflammatory or metabolic disorders, the underlying mechanism by which NLRP3 inflammasome signaling is initiated or potentiated remains poorly understood. Much attention is being paid to mitochondria as a regulator of NLRP3 inflammasome activation, but little is known about the role of mitochondrial dynamics for the inflammasome pathway. Here, we present evidence that aberrant mitochondrial elongation caused by the knockdown of dynamin-related protein 1 (Drp1) lead to a marked increase in NLRP3-dependent caspase-1 activation and interleukin-1-beta secretion in mouse bone marrow-derived macrophages. Conversely, carbonyl cyanide m-chlorophenyl hydrazone, a chemical inducer of mitochondrial fission, clearly attenuated NLRP3 inflammasome assembly and activation. Augmented activation of NLRP3 inflammasome by mitochondrial elongation is not resulted from the increased mitochondrial damages of Drp1-knockdown cells. Notably, enhanced extracellular signal-regulated kinase (ERK) signaling in Drp1-knockdown macrophages is implicated in the potentiation of NLRP3 inflammasome activation, possibly via mediating mitochondrial localization of NLRP3 to facilitate the assembly of NLRP3 inflammasome. Taken together, our results provide a molecular insight into the importance of mitochondrial dynamics in potentiating NLRP3 inflammasome activation, leading to aberrant inflammation.

Stimulator of IFN genes–mediated DNA‐sensing pathway is suppressed by NLRP3 agonists and regulated by mitofusin 1 and TBC1D15, mitochondrial dynamics mediators

“…The caspase-1 inhibitor, YVAD, has been previously shown to block mitochondrial fission induced by LPS plus ATP or nigericin, which suggests the involvement of caspase-1 in this process (31). In caspase-1-deficient BMDMs, however, we found that mitochondrial fission still occurred in response to ATP or nigericin, and that IFN-b induction was not rescued (Fig.…”

“…We noticed that these stimuli also trigger mitochondrial fragmentation (31,33). Although the previous studies did not examine whether ATP or nigericin alone could induce mitochondrial fragmentation, we observed that these monotreatments were sufficient to induce mitochondrial fragmentation in BMDMs (Fig.…”

“…Mitochondrial dynamics and membrane potential have been shown to regulate RLR and NLRP3 inflammasome activation (27,28). Conversely, previous studies have demonstrated that NLRP3 inflammasome activation triggered mitochondrial damage, as assessed by the dissipation of the mitochondrial membrane potential (MMP) (29)(30)(31)(32)(33). Of interest, a recent study found that inhibitors of the mitochondrial respiratory chain or dissipation of MMP suppressed STING-mediated type I IFN production (34); therefore, we hypothesized a cross-regulation of the STING pathway by NLRP3 activation, likely via induction of mitochondrial damage.…”

The mitochondrial dynamics in cancer and immune-surveillance

“…MAVS interaction with Mfn-1 and -2 promotes mitochondrial elongation [183], which in turn favours MAVS association with ER-associated Stimulator of Interferon Genes (STING) protein, an interaction essential for the activation of downstream transcription factors [183]. The inflammasome requirement of mitochondrial elongation has been recently demonstrated also in Drp1-silenced macrophages [184] and is correlated with reduced Opa-1 levels in rat [185]. Additionally, receptor-interacting protein kinase -1 and -3 (RIPK1/3)-dependent and lipopolysaccharide (LPS)-dependent inflammasome activation, and cytokine production upon viral infection, requires Drp1-dependent mitochondrial fission to induce mitochondrial damage and generate ROS [186,187].…”

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

“…increases mitochondrial fragmentation (27,55,56), with the fragmentation resulting in part from the high production of reactive oxygen species that occurs with activation (56 -59). We thus reasoned that the fragmented mitochondrial morphology in Irgm1-deficient macrophages may be a result of the metabolic changes in those cells in the context of high ROS levels.…”