The rOX‐stars of inflammation: links between the inflammasome and mitochondrial meltdown

Holley, Caroline L.; Schroder, Kate

doi:10.1002/cti2.1109

Cited by 36 publications

(24 citation statements)

References 116 publications

(239 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MAVS facilitates NLRP3 binding with ASC and pro-caspase 1 [ 147 , 153 ]. In addition, ER and mitochondria associated membrane are found to be the potential site for NLRP3 assembly [ 154 ]. Reports of subcellular localization of ASC varies significantly [ 53 ], including mitochondria [ 155 ], cytosol [ 150 ] and nucleus [ 156 ].…”

Section: Mitochondrial Ros Systems Serve As the Central Hub For Connementioning

confidence: 99%

“…Furthermore, ROS activate NLRP3 inflammasome via direct and indirect ways. Studies found that increased ROS level induced mitochondrial DNA damage is also an indirect pathway for NLRP3 inflammasome activation by ROS [ 152 , 154 ]. In high level of ROS, thioredoxin-interacting protein (TXNIP) is dissociated with TRX and activates NLRP3 inflammasome [ 157 ].…”

Section: Mitochondrial Ros Systems Serve As the Central Hub For Connementioning

confidence: 99%

See 1 more Smart Citation

ROS systems are a new integrated network for sensing homeostasis and alarming stresses in organelle metabolic processes

et al. 2020

View full text Add to dashboard Cite

Reactive oxygen species (ROS) are critical for the progression of cardiovascular diseases, inflammations and tumors. However, the mechanisms of how ROS sense metabolic stress, regulate metabolic pathways and initiate proliferation, inflammation and cell death responses remain poorly characterized. In this analytic review, we concluded that: 1) Based on different features and functions, eleven types of ROS can be classified into seven functional groups: metabolic stress-sensing, chemical connecting, organelle communication, stress branch-out, inflammasome-activating, dual functions and triple functions ROS. 2) Among the ROS generation systems, mitochondria consume the most amount of oxygen; and nine types of ROS are generated; thus, mitochondrial ROS systems serve as the central hub for connecting ROS with inflammasome activation, trained immunity and immunometabolic pathways. 3) Increased nuclear ROS production significantly promotes cell death in comparison to that in other organelles. Nuclear ROS systems serve as a convergent hub and decision-makers to connect unbearable and alarming metabolic stresses to inflammation and cell death. 4) Balanced ROS levels indicate physiological homeostasis of various metabolic processes in subcellular organelles and cytosol, while imbalanced ROS levels present alarms for pathological organelle stresses in metabolic processes. Based on these analyses, we propose a working model that ROS systems are a new integrated network for sensing homeostasis and alarming stress in metabolic processes in various subcellular organelles. Our model provides novel insights on the roles of the ROS systems in bridging metabolic stress to inflammation, cell death and tumorigenesis; and provide novel therapeutic targets for treating those diseases. (Word count: 246).

show abstract

Section: Mitochondrial Ros Systems Serve As the Central Hub For Connementioning

confidence: 99%

Section: Mitochondrial Ros Systems Serve As the Central Hub For Connementioning

confidence: 99%

ROS systems are a new integrated network for sensing homeostasis and alarming stresses in organelle metabolic processes

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The major job of the NLRP3 pathway is to detect dangers to membrane integrity and cellular viability and to trigger alarm via IL-1β secretion [22]. Mitochondria are central to cellular viability and metabolic homeostasis, and, as such, mitochondrial dysfunction has been implicated in NLRP3 inflammasome activation by various mechanisms, reviewed in [51]. While in our imaging experiments staining of macrophage nuclei by the dye Draq7 occurred after ASC speck formation, loss of plasma membrane integrity must precede influx of Draq7 into cells and our imaging does not report on the exact timing of the initial damage to the membrane.…”

Section: Plos Pathogensmentioning

confidence: 99%

Metabolic competition between host and pathogen dictates inflammasome responses to fungal infection

et al. 2020

View full text Add to dashboard Cite

The NLRP3 inflammasome has emerged as a central immune regulator that senses virulence factors expressed by microbial pathogens for triggering inflammation. Inflammation can be harmful and therefore this response must be tightly controlled. The mechanisms by which immune cells, such as macrophages, discriminate benign from pathogenic microbes to control the NLRP3 inflammasome remain poorly defined. Here we used live cell imaging coupled with a compendium of diverse clinical isolates to define how macrophages respond and activate NLRP3 when faced with the human yeast commensal and pathogen Candida albicans. We show that metabolic competition by C. albicans, rather than virulence traits such as hyphal formation, activates NLRP3 in macrophages. Inflammasome activation is triggered by glucose starvation in macrophages, which occurs when fungal load increases sufficiently to outcompete macrophages for glucose. Consistently, reducing Candida's ability to compete for glucose and increasing glucose availability for macrophages tames inflammatory responses. We define the mechanistic requirements for glucose starvationdependent inflammasome activation by Candida and show that it leads to inflammatory cytokine production, but it does not trigger pyroptotic macrophage death. Pyroptosis occurs only with some Candida isolates and only under specific experimental conditions, whereas inflammasome activation by glucose starvation is broadly relevant. In conclusion, macrophages use their metabolic status, specifically glucose metabolism, to sense fungal metabolic activity and activate NLRP3 when microbial load increases. Therefore, a major consequence of Candida-induced glucose starvation in macrophages is activation of inflammatory responses, with implications for understanding how metabolism modulates inflammation in fungal infections.

show abstract

“…Prior studies of mouse Irgm proteins almost exclusively focused on Irgm1 and revealed shared functions of mouse Irgm1 and human IRGM, especially regarding the regulation of mitochondrial dynamics . Mitochondrial dysfunction and the associated release of oxidized mitochondrial DNA provide compelling molecular models to account for the increased inflammation observed in Irgm1-deficient cells and animals, and may also underlie some of the autoinflammation associated with human IRGM disease alleles , Holley & Schroder, 2020. In addition to controlling mitochondrial remodeling and autophagy, Golgi-resident human IRGM also regulates Golgi fragmentation in response to viral infections (Hansen, Johnsen et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Dynamin-related Irgm proteins modulate LPS-induced caspase-4 activation and septic shock

Finethy

Dockterman

Kutsch

et al. 2020

Preprint

View full text Add to dashboard Cite

Inflammation associated with gram-negative bacterial infections is often instigated by the bacterial cell wall component lipopolysaccharide (LPS). LPS-induced inflammation and resulting life-threatening sepsis are mediated by the two distinct LPS receptors TLR4 and caspase-4. Whereas the regulation of TLR4 activation by extracellular and phago-endosomal LPS has been studied in great detail, auxiliary host factors that specifically modulate recognition of cytosolic LPS by caspase-4 are largely unknown. This study identifies dynamin-related membrane remodeling proteins belonging to the family of Immunity related GTPases M clade (IRGM) as negative regulators of caspase-4 activation in macrophages. Phagocytes lacking expression of mouse isoform Irgm2aberrantly activate caspase-4-dependent inflammatory responses when exposed to extracellular LPS, bacterial outer membrane vesicles or gram-negative bacteria.Consequently, Irgm2-deficient mice display increased susceptibility to caspase-4mediated septic shock in vivo. This Irgm2 phenotype is partly reversed by the simultaneous genetic deletion of the two additional Irgm paralogs Irgm1 and Irgm3, indicating that dysregulated Irgm isoform expression disrupts intracellular LPS processing pathways that limit LPS availability for caspase-4 activation.

show abstract

The rOX‐stars of inflammation: links between the inflammasome and mitochondrial meltdown

Cited by 36 publications

References 116 publications

ROS systems are a new integrated network for sensing homeostasis and alarming stresses in organelle metabolic processes

ROS systems are a new integrated network for sensing homeostasis and alarming stresses in organelle metabolic processes

Metabolic competition between host and pathogen dictates inflammasome responses to fungal infection

Dynamin-related Irgm proteins modulate LPS-induced caspase-4 activation and septic shock

Contact Info

Product

Resources

About