Mechanism and Regulation of NLRP3 Inflammasome Activation

He, Yuan; Hara, Hideki; Núñez, Gabriel

doi:10.1016/j.tibs.2016.09.002

Cited by 2,182 publications

(1,969 citation statements)

References 82 publications

Supporting

Mentioning

1,887

Contrasting

Unclassified

Order By: Relevance

“…The NLRP3 inflammasome is formed after indirect sensing of both non-sterile insults derived from pathogens (PAMPs) and sterile stressors (DAMPs). These range from bacterial products, mitochondrial DNA, viruses, and ATP to particulate matter such as crystals and amyloids [6,7,8] . Before a functional NLRP3 inflammasome can be formed, however, transcriptional and post-translational mechanisms must achieve a reasonable level of NLRP3 expression within the cell, and a suitable level of pro-IL-1 must also accumulate -this is a process known as inflammasome priming, or 'signal 1' (Figure 1, Key Figure).…”

mentioning

confidence: 99%

Inflammasome Priming in Sterile Inflammatory Disease

Patel

Carroll

Galván-Peña

et al. 2017

Trends in Molecular Medicine

211

167

View full text Add to dashboard Cite

mentioning

confidence: 99%

Inflammasome Priming in Sterile Inflammatory Disease

Patel

Carroll

Galván-Peña

et al. 2017

Trends in Molecular Medicine

211

167

View full text Add to dashboard Cite

“…The most studied inflammasome structure is the canonical NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome, which is activated by several microbial stimuli as well as by endogenous danger signals, including ATP and monosodium urate (7). The NLRP3 inflammasome activates caspase-1, which in turn facilitates the proteolytic processing and secretion of pro-inflammatory cytokines IL-1␤ and IL-18.…”

mentioning

confidence: 99%

Global Characterization of Protein Secretion from Human Macrophages Following Non-canonical Caspase-4/5 Inflammasome Activation

Lorey

Rossi

Eklund

et al. 2017

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

Gram-negative bacteria are associated with a wide spectrum of infectious diseases in humans. Inflammasomes are cytosolic protein complexes that are assembled when the cell encounters pathogens or other harmful agents. The non-canonical caspase-4/5 inflammasome is activated by Gram-negative bacteria-derived lipopolysaccharide (LPS) and by endogenous oxidized phospholipids. Protein secretion is a critical component of the innate immune response. Here, we have used label-free quantitative proteomics to characterize global protein secretion in response to non-canonical inflammasome activation upon intracellular LPS recognition in human primary macrophages. Before proteomics, the total secretome was separated into two fractions, enriched extracellular vesicle (EV) fraction and rest-secretome (RS) fraction using size-exclusion centrifugation. We identified 1048 proteins from the EV fraction and 1223 proteins from the RS fraction. From these, 640 were identified from both fractions suggesting that the non-canonical inflammasome activates multiple, partly overlapping protein secretion pathways. We identified several secreted proteins that have a critical role in host response against severe Gramnegative bacterial infection. The soluble secretome (RS fraction) was highly enriched with inflammation-associated proteins upon intracellular LPS recognition. Several ribosomal proteins were highly abundant in the EV fraction upon infection, and our data strongly suggest that secretion of translational machinery and concomitant inhibition of translation are important parts of host response against Gram-negative bacteria sensing caspase-4/5 inflammasome. Intracellular recognition of LPS resulted in the secretion of two metalloproteinases, a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and MMP14, in the enriched EV fraction. ADAM10 release was associated with the secretion of TNF, a key inflammatory cytokine, and M-CSF, an important growth factor for myeloid cells probably through ADAM10-dependent membrane shedding of these cytokines. Caspase-4/5 inflammasome activation also resulted in secretion of danger-associated molecules S100A8 and prothymosin-␣ in the enriched EV fraction. Both S100A8 and prothymosin-␣ are ligands for toll-like receptor 4 recognizing extracellular LPS, and they may contribute to endotoxic shock during non-canonical inflammasome activation. Molecular & Cellular Proteomics 16: 10.1074/mcp.M116.064840, S187-S199, 2017.

show abstract

“…The inflammasome assembly leads to caspase-1 activation that converts the cytokine precursors pro-IL-1β and pro-IL-18 into mature and bioactive form IL-1β and IL-18, respectively, which are two pro-inflammatory cytokines involved in neuroimmunomodulation, neuroinflammation and neurodegeneration. These cytokines trigger signaling cascades that culminate in a type of inflammatory neuronal death termed pyroptosis [114,115,117,118]. There are two well-established pathways for NLRP3 inflammasome activation and an alternative NLPR3 inflammasome activation pathway was recently described that occurs exclusively in human monocytes [115,118,119].…”

Section: Inflammasome Activationmentioning

confidence: 99%

The ups and downs of cellular stress: the “MAM hypothesis” for Bipolar disorder pathophysiology

Pereira¹,

Resende²,

Morais³

et al. 2017

IJCNMH

View full text Add to dashboard Cite

Mental health problems constitute the largest single source of world economic burden, with an estimated global cost greater than cardiovascular disease, cancer or diabetes individually. In the European Union mental disorders affect millions of people and these numbers are expected to rise as result of Europe's ageing population. Given the biological causes of many of these disorders, most studies focus on their molecular basis. Bipolar disorder (BD) is characterized by mood swings between depression and mania resulting in cognitive and functional impairments that require lifetime treatment. Recurrent mood episodes, residual symptoms, functional impairment, psychosocial disability with high rates of divorce, unemployment, drug abuse and suicide attempting, and significant medical comorbidities such as metabolic and cardiovascular diseases cannot be efficiently controlled even with proper use of current treatments. Moreover, delayed diagnosis/misdiagnosis is frequent because reliable biomarkers are absent. Therefore, a better understanding of BD pathophysiology is a prerequisite for the design of new drugs and their implementation in clinical practice as well as to develop biomarkers for a more accurate and earlier diagnosis and/or evaluation of therapeutic response. This review summarises the association between decreased cellular resilience towards stress and BD. Since the key stress-response mediator Mitochondria-Associated Membranes (MAMs) modulate several BD relevant processes such as mitochondrial dysfunction and oxidative stress, Ca 2+ deregulation and cytoskeleton abnormalities, endoplasmic reticulum stress responses, loss of proteostasis and inflammasome activation, we propose the "MAM hypothesis" for BD pathophysiology. Targeting MAM-associated signaling pathways can be a promising investigation avenue to identify novel therapeutic strategies.Keywords: Bipolar disorder, Endoplasmic reticulum, Mitochondria, Mitochondria-associated membranes, Cellular resilience, Cellular stress, Plasticity. Bipolar DisorderBD is a chronic psychiatric illness with a remitting course, affecting 2.4% of the general population [1], characterized by mood swings between manic and depressive states that result in cognitive and functional impairments, high health care costs and premature mortality [2,3]. BD is the sixth leading cause of disability worldwide responsible for loss of more disability-adjusted life-years than all forms of cancer and major neurological conditions [4]. BD is associated with greatly impaired quality of life and increased physical health burden [5]. Moreover, BD patients tend to have high rates of divorce, unemployment, drug abuse and crime as consequence of impaired social cognition, and its impact on patients can be devastating, with approximately 23% of patients with BD reported having suicide attempts [6]. Moreover, individuals with BD diagnosis have a high risk of medical comorbidities such as metabolic (diabetes, obesity and metabolic syndrome) and cardiovascular disorders [7].Current knowl...

show abstract

Mechanism and Regulation of NLRP3 Inflammasome Activation

Cited by 2,182 publications

References 82 publications

Inflammasome Priming in Sterile Inflammatory Disease

Inflammasome Priming in Sterile Inflammatory Disease

Global Characterization of Protein Secretion from Human Macrophages Following Non-canonical Caspase-4/5 Inflammasome Activation

The ups and downs of cellular stress: the “MAM hypothesis” for Bipolar disorder pathophysiology

Contact Info

Product

Resources

About