Mitochondrial DNA, oxidants, and innate immunity

Piantadosi, Claude A.

doi:10.1016/j.freeradbiomed.2020.01.013

Cited by 40 publications

(22 citation statements)

References 99 publications

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“…In recent years, mitochondria have been shown to play an essential role in the activation of the NLRP3 inflammasome (79,80). Mitochondria are an ideal platform to assemble the NLRP3 inflammasome.…”

Section: Reactive Oxygen Species and Mitochondrial Dysfunctionmentioning

confidence: 99%

The NLRP3 Inflammasome and Its Role in T1DM

Sun

Pang

et al. 2020

Front. Immunol.

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The NLRP3 (nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome is a protein complex expressed in cells. It detects danger signals and induces the production of active caspase-1 and the maturation and release of IL (interleukin)-33, IL-18, IL-1β and other cytokines. T1DM (type 1 diabetes mellitus) is defined as a chronic autoimmune disorder characterized by the autoreactive T cell-mediated elimination of insulin-positive pancreatic beta-cells. Although the exact underlying mechanisms are obscure, researchers have proposed that both environmental and genetic factors are involved in the pathogenesis of T1DM. Furthermore, immune responses, including innate and adaptive immunity, play an important role in this process. Recently, the NLRP3 inflammasome, a critical component of innate immunity, was reported to be associated with T1DM. Here, we review the assembly and function of the NLRP3 inflammasome. In addition, the activation and regulatory mechanisms that enhance or attenuate NLRP3 inflammasome activation are discussed. Finally, we focus on the relationship between the NLRP3 inflammasome and T1DM, as well as its potential value for clinical use.

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Section: Reactive Oxygen Species and Mitochondrial Dysfunctionmentioning

confidence: 99%

The NLRP3 Inflammasome and Its Role in T1DM

Sun

Pang

et al. 2020

Front. Immunol.

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“…The role of TLR9‐mediated IL1 expression is increasingly recognized in the pathogenesis of diseases associated with sterile inflammation 1–4,101 . Given the strength of these findings, targeting IL1 activity has been proposed as a therapeutic intervention to limit inflammatory injury 2 .…”

Section: Discussionmentioning

confidence: 99%

CpG‐ODN‐mediated TLR9 innate immune signalling and calcium dyshomeostasis converge on the NFκB inhibitory protein IκBβ to drive IL1α and IL1β expression

et al. 2020

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Sterile inflammation contributes to many pathological states associated with mitochondrial injury. Mitochondrial injury disrupts calcium homeostasis and results in the release of CpG-rich mitochondrial DNA. The role of CpG-stimulated TLR9 innate immune signalling and sterile inflammation is well studied; however, how calcium dyshomeostasis affects this signalling is unknown. Therefore, we interrogated the relationship besween intracellular calcium and CpG-induced TLR9 signalling in murine macrophages. We found that CpG-ODN-induced NFjB-dependent IL1a and IL1b expression was significantly attenuated by both calcium chelation and calcineurin inhibition, a finding mediated by inhibition of degradation of the NFjB inhibitory protein IjBb. In contrast, calcium ionophore exposure increased CpG-induced IjBb degradation and IL1a and IL1b expression. These results demonstrate that through its effect on IjBb degradation, increased intracellular Ca 2+ drives a pro-inflammatory TLR9-mediated innate immune response. These results have implications for the study of innate immune signalling downstream of mitochondrial stress and injury.

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“…The mechanisms by which mitochondrial abnormalities can result in an altered immune profile are poorly understood, although several studies have demonstrated that dysfunctional or failing mitochondria can release mitochondrial-derived damage –associated molecular patterns (72) and that these are associated with chronic inflammation in conditions such as ageing and several degenerative diseases. Inflammation can occur in the absence of infection and it has been proposed that mitochondria contribute to such ‘sterile inflammation’(73). No difference in mitochondrial superoxide or hydrogen peroxide generation by mitochondria of patients with ME/CFS was seen compared with HCs, either in State 1 (with endogenous substrates) or with the addition of glutamate/maleate or succinate.…”

Section: Discussionmentioning

confidence: 99%

Discriminatory cytokine profiles predict muscle function, fatigue and cognitive function in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Gusnanto

Earl

Sakellariou

et al. 2020

Preprint

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Myalgic Encephalomyelitis (ME) /Chronic Fatigue Syndrome (CFS) is a severely debilitating and complex illness of uncertain aetiology, affecting the lives of millions and characterised by prolonged fatigue. The initiating factors and mechanisms leading to chronic debilitating muscle fatigue in ME/CFS are unknown and are complicated by the time required for diagnosis. Both mitochondrial dysfunction and inflammation have been proposed to be central to the pathogenesis of ME/CFS. This original and extensive study demonstrated that although there was little dysfunction evident in the muscle mitochondria of patients with ME/CFS, particular blood plasma and skeletal muscle cytokines, when adjusted for age, gender and cytokine interactions could predict both diagnosis and a number of measures common to patients with ME/CFS. These included MVC and perceived fatigue as well as cognitive indices such as pattern and verbal reaction times. We employed advanced multivariate analyses to cytokine profiles that leverages covariation and intrinsic redundancy to identify patterns of immune signaling that can be evaluated for their predictions of disease phenotype. The current study identified discriminatory cytokine profiles that can be sufficiently used to distinguish HCs from patients with ME/CFS and provides compelling evidence that a limited number of cytokines are associated with diagnosis and fatigue. Moreover, this study demonstrates significant potential of using multiplex cytokine profiles and bioinformatics as diagnostic tools for ME/CFS, potentiating the possibility of not only diagnosis, but also being able to individually personalise therapies.

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Mitochondrial DNA, oxidants, and innate immunity

Cited by 40 publications

References 99 publications

The NLRP3 Inflammasome and Its Role in T1DM

The NLRP3 Inflammasome and Its Role in T1DM

CpG‐ODN‐mediated TLR9 innate immune signalling and calcium dyshomeostasis converge on the NFκB inhibitory protein IκBβ to drive IL1α and IL1β expression

Discriminatory cytokine profiles predict muscle function, fatigue and cognitive function in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

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