The septin modifier, forchlorfenuron, activates NLRP3 via a potassium-independent mitochondrial axis.

The Nod-like receptor protein 3 (NLRP3) inflammasome is activated by stimuli that induce perturbations in cell homeostasis, which commonly converge on cellular potassium efflux. NLRP3 has thus emerged as a sensor for ionic flux. Here, we identify forchlorfenuron (FCF) as an inflammasome activator that triggers NLRP3 signaling independently of potassium efflux. FCF triggers the rearrangement of septins, key cytoskeletal proteins that regulate mitochondrial function. We report that FCF triggered the rearrangement of SEPT2 into tubular aggregates and stimulated SEPT2-independent NLRP3 inflammasome signaling. Similar to imiquimod, FCF induced the collapse of the mitochondrial membrane potential and mitochondrial respiration. FCF thereby joins the imidazoquinolines as a structurally distinct class of molecules that triggers NLRP3 inflammasome signaling independent of potassium efflux, likely by inducing mitochondrial damage.

Reversing the mitochondrial hex that bewitches NLRP3.

Hexokinase dissociation from mitochondria triggers calcium-induced oligomerization of VDAC within the outer mitochondrial membrane, leading to NLRP3 recruitment and inflammasome signaling (see related Research Article by Baik et al.).

Mitochondrial dynamics in macrophages: divide to conquer or unite to survive?

Mitochondria have long been appreciated as the metabolic hub of cells. Emerging evidence also posits these organelles as hubs for innate immune signalling and activation, particularly in macrophages. Macrophages are front-line cellular defenders against endogenous and exogenous threats in mammals. These cells use an array of receptors and downstream signalling molecules to respond to a diverse range of stimuli, with mitochondrial biology implicated in many of these responses. Mitochondria have the capacity to both divide through mitochondrial fission and coalesce through mitochondrial fusion. Mitochondrial dynamics, the balance between fission and fusion, regulate many cellular functions, including innate immune pathways in macrophages. In these cells, mitochondrial fission has primarily been associated with pro-inflammatory responses and metabolic adaptation, so can be considered as a combative strategy utilised by immune cells. In contrast, mitochondrial fusion has a more protective role in limiting cell death under conditions of nutrient starvation. Hence, fusion can be viewed as a cellular survival strategy. Here we broadly review the role of mitochondria in macrophage functions, with a focus on how regulated mitochondrial dynamics control different functional responses in these cells.

Parkinson's disease: connecting mitochondria to inflammasomes.

Activated microglia foster a neurotoxic, inflammatory environment in the mammalian central nervous system (CNS) that drives the pathology of neurodegenerative diseases including Parkinson's disease (PD). Moreover, mitochondrial fission promotes microglial inflammatory responses in vitro. Given that the NLRP3 inflammasome and mitochondria are central regulators of both inflammation and PD, we explore potential functions for the NLRP3 inflammasome and mitochondrial dynamics in PD. Specifically, we propose that inducible microglial mitochondrial fission can promote NLRP3-dependent neuroinflammation in hereditary and idiopathic PD. Further in-depth exploration of this topic can prompt valuable discoveries of the underlying molecular mechanisms of PD neuroinflammation, identify novel candidate anti-inflammatory therapeutics for PD, and ideally provide better outcomes for PD patients.

Come on mtDNA, light my fire.

Oxidized mitochondrial DNA (ox-mtDNA) activates NLRP3 inflammasome signaling through an ill-defined mechanism. In this issue of Immunity, Xian et al. reveal FEN1 endonuclease cleaves ox-mtDNA into fragments that escape mitochondria, igniting NLRP3 and cGAS-STING signaling and inflammation.