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19 pages, 4878 KiB

Open AccessArticle

Parsing the IL-37-Mediated Suppression of Inflammasome Function

by Ina Rudloff, Holly K. Ung, Jennifer K. Dowling, Ashley Mansell, Laura D’Andrea, Andrew M. Ellisdon, James C. Whisstock, Philip J. Berger, Claudia A. Nold-Petry and Marcel F. Nold

Cells 2020, 9(1), 178; https://doi.org/10.3390/cells9010178 - 10 Jan 2020

Cited by 22 | Viewed by 5537

Abstract

Interleukin (IL)-37 is a member of the IL-1 family of cytokines. Although its broad anti-inflammatory properties are well described, the effects of IL-37 on inflammasome function remain poorly understood. Performing gene expression analyses, ASC oligomerization/speck assays and caspase-1 assays in bone marrow-derived macrophages [...] Read more.

Interleukin (IL)-37 is a member of the IL-1 family of cytokines. Although its broad anti-inflammatory properties are well described, the effects of IL-37 on inflammasome function remain poorly understood. Performing gene expression analyses, ASC oligomerization/speck assays and caspase-1 assays in bone marrow-derived macrophages (BMDM), and employing an in vivo endotoxemia model, we studied how IL-37 affects the expression and maturation of IL-1β and IL-18, inflammasome activation, and pyroptosis in detail. IL-37 inhibited IL-1β production by NLRP3 and AIM2 inflammasomes, and IL-18 production by the NLRP3 inflammasome. This inhibition was partially attributable to effects on gene expression: whereas IL-37 did not affect lipopolysaccharide (LPS)-induced mRNA expression of Il18 or inflammasome components, IL-37-transgenic BMDM displayed an up to 83% inhibition of baseline and LPS-stimulated Il1b compared to their wild-type counterparts. Importantly, we observed that IL-37 suppresses nigericin- and silica-induced ASC oligomerization/speck formation (a step in inflammasome activation and subsequent caspase-1 activation), and pyroptosis (−50%). In mice subjected to endotoxemia, IL-37 inhibited plasma IL-1β (−78% compared to wild-type animals) and IL-18 (−61%). Thus, our study adds suppression of inflammasome activity to the portfolio of anti-inflammatory pathways employed by IL-37, highlighting this cytokine as a potential tool for treating inflammasome-driven diseases. Full article

(This article belongs to the Special Issue Mechanisms of Inflammasome Activation)

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18 pages, 4005 KiB

Open AccessArticle

DROSHA-Dependent AIM2 Inflammasome Activation Contributes to Lung Inflammation during Idiopathic Pulmonary Fibrosis

by Soo Jung Cho, Kyoung Sook Hong, Ji Hun Jeong, Mihye Lee, Augustine M. K. Choi, Heather W. Stout-Delgado and Jong-Seok Moon

Cells 2019, 8(8), 938; https://doi.org/10.3390/cells8080938 - 20 Aug 2019

Cited by 21 | Viewed by 5058

Abstract

Idiopathic pulmonary fibrosis (IPF) has been linked to chronic lung inflammation. Drosha ribonuclease III (DROSHA), a class 2 ribonuclease III enzyme, plays a key role in microRNA (miRNA) biogenesis. However, the mechanisms by which DROSHA affects the lung inflammation during idiopathic pulmonary fibrosis [...] Read more.

Idiopathic pulmonary fibrosis (IPF) has been linked to chronic lung inflammation. Drosha ribonuclease III (DROSHA), a class 2 ribonuclease III enzyme, plays a key role in microRNA (miRNA) biogenesis. However, the mechanisms by which DROSHA affects the lung inflammation during idiopathic pulmonary fibrosis (IPF) remain unclear. Here, we demonstrate that DROSHA regulates the absent in melanoma 2 (AIM2) inflammasome activation during idiopathic pulmonary fibrosis (IPF). Both DROSHA and AIM2 protein expression were elevated in alveolar macrophages of patients with IPF. We also found that DROSHA and AIM2 protein expression were increased in alveolar macrophages of lung tissues in a mouse model of bleomycin-induced pulmonary fibrosis. DROSHA deficiency suppressed AIM2 inflammasome-dependent caspase-1 activation and interleukin (IL)-1β and IL-18 secretion in primary mouse alveolar macrophages and bone marrow-derived macrophages (BMDMs). Transduction of microRNA (miRNA) increased the formation of the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) specks, which is required for AIM2 inflammasome activation in BMDMs. Our results suggest that DROSHA promotes AIM2 inflammasome activation-dependent lung inflammation during IPF. Full article

(This article belongs to the Special Issue Mechanisms of Inflammasome Activation)

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12 pages, 1243 KiB

Open AccessArticle

Circulating Cell-Free mtDNA Contributes to AIM2 Inflammasome-Mediated Chronic Inflammation in Patients with Type 2 Diabetes

by Jung Hwan Bae, Seung Jo II, Seong Jin Kim, Jong Min Lee, Ji Hun Jeong, Jeong Suk Kang, Nam-Jun Cho, Sang Soo Kim, Eun Young Lee and Jong-Seok Moon

Cells 2019, 8(4), 328; https://doi.org/10.3390/cells8040328 - 8 Apr 2019

Cited by 97 | Viewed by 7126

Abstract

Mitochondrial dysfunction has been implicated in the pathogenesis of insulin resistance and type 2 diabetes. Damaged mitochondria DNA (mtDNA) may have a role in regulating hyperglycemia during type 2 diabetes. Circulating cell-free mitochondria DNA (ccf-mtDNA) was found in serum and plasma from patients [...] Read more.

Mitochondrial dysfunction has been implicated in the pathogenesis of insulin resistance and type 2 diabetes. Damaged mitochondria DNA (mtDNA) may have a role in regulating hyperglycemia during type 2 diabetes. Circulating cell-free mitochondria DNA (ccf-mtDNA) was found in serum and plasma from patients and has been linked to the prognosis factors in various human diseases. However, the role of ccf-mtDNA in chronic inflammation in type 2 diabetes is unclear. In this study, we hypothesized that the ccf-mtDNA levels are associated with chronic inflammation in patients with type 2 diabetes. The mtDNA levels were elevated in the plasma from patients with type 2 diabetes compared to healthy subjects. The elevated mtDNA levels were associated with interleukin-1β (IL-1β) levels in patients with type 2 diabetes. The mtDNA, from patients with type 2 diabetes, induced absent in melanoma 2 (AIM2) inflammasome-dependent caspase-1 activation and IL-1β and IL-18 secretion in macrophages. Our results suggest that the ccf-mtDNA might contribute to AIM2 inflammasome-mediated chronic inflammation in type 2 diabetes. Full article

(This article belongs to the Special Issue Mechanisms of Inflammasome Activation)

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15 pages, 2259 KiB

Open AccessArticle

Human Lung Cell Pyroptosis Following Traumatic Brain Injury

by Nadine A. Kerr, Juan Pablo de Rivero Vaccari, Oliver Umland, M. Ross Bullock, Gregory E. Conner, W. Dalton Dietrich and Robert W. Keane

Cells 2019, 8(1), 69; https://doi.org/10.3390/cells8010069 - 18 Jan 2019

Cited by 49 | Viewed by 5218

Abstract

Approximately 30% of traumatic brain injured patients suffer from acute lung injury or acute respiratory distress syndrome. Our previous work revealed that extracellular vesicle (EV)-mediated inflammasome signaling plays a crucial role in the pathophysiology of traumatic brain injury (TBI)-induced lung injury. Here, serum-derived [...] Read more.

Approximately 30% of traumatic brain injured patients suffer from acute lung injury or acute respiratory distress syndrome. Our previous work revealed that extracellular vesicle (EV)-mediated inflammasome signaling plays a crucial role in the pathophysiology of traumatic brain injury (TBI)-induced lung injury. Here, serum-derived EVs from severe TBI patients were analyzed for particle size, concentration, origin, and levels of the inflammasome component, an apoptosis-associated speck-like protein containing a caspase-recruiting domain (ASC). Serum ASC levels were analyzed from EV obtained from patients that presented lung injury after TBI and compared them to EV obtained from patients that did not show any signs of lung injury. EVs were co-cultured with lung human microvascular endothelial cells (HMVEC-L) to evaluate inflammasome activation and endothelial cell pyroptosis. TBI patients had a significant increase in the number of serum-derived EVs and levels of ASC. Severe TBI patients with lung injury had a significantly higher level of ASC in serum and serum-derived EVs compared to individuals without lung injury. Only EVs isolated from head trauma patients with gunshot wounds were of neural origin. Delivery of serum-derived EVs to HMVEC-L activated the inflammasome and resulted in endothelial cell pyroptosis. Thus, serum-derived EVs and inflammasome proteins play a critical role in the pathogenesis of TBI-induced lung injury, supporting activation of an EV-mediated neural-respiratory inflammasome axis in TBI-induced lung injury. Full article

(This article belongs to the Special Issue Mechanisms of Inflammasome Activation)

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Review

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16 pages, 744 KiB

Open AccessReview

The Role of Inflammasome-Dependent and Inflammasome-Independent NLRP3 in the Kidney

by Yang Gyun Kim, Su-Mi Kim, Ki-Pyo Kim, Sang-Ho Lee and Ju-Young Moon

Cells 2019, 8(11), 1389; https://doi.org/10.3390/cells8111389 - 5 Nov 2019

Cited by 105 | Viewed by 8950

Abstract

Cytoplasmic nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) forms an inflammasome with apoptosis-associated speck-like protein containing a CARD (ASC) and pro-caspase-1, which is followed by the cleavage of pro-caspase-1 to active caspase-1 and ultimately the activation of IL-1β and IL-18 and induction of [...] Read more.

Cytoplasmic nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) forms an inflammasome with apoptosis-associated speck-like protein containing a CARD (ASC) and pro-caspase-1, which is followed by the cleavage of pro-caspase-1 to active caspase-1 and ultimately the activation of IL-1β and IL-18 and induction of pyroptosis in immune cells. NLRP3 activation in kidney diseases aggravates inflammation and subsequent fibrosis, and this effect is abrogated by genetic or pharmacologic deletion of NLRP3. Inflammasome-dependent NLRP3 mediates the progression of kidney diseases by escalating the inflammatory response in immune cells and the cross-talk between immune cells and renal nonimmune cells. However, recent studies have suggested that NLRP3 has several inflammasome-independent functions in the kidney. Inflammasome-independent NLRP3 regulates apoptosis in tubular epithelial cells by interacting with mitochondria and mediating mitochondrial reactive oxygen species production and mitophagy. This review will summarize the mechanisms by which NLRP3 functions in the kidney in both inflammasome-dependent and inflammasome-independent ways and the role of NLRP3 and NLRP3 inhibitors in kidney diseases. Full article

(This article belongs to the Special Issue Mechanisms of Inflammasome Activation)

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26 pages, 19095 KiB

Open AccessReview

Inflammasome-Mediated Inflammation in Liver Ischemia-Reperfusion Injury

by Mónica B. Jiménez-Castro, María Eugenia Cornide-Petronio, Jordi Gracia-Sancho and Carmen Peralta

Cells 2019, 8(10), 1131; https://doi.org/10.3390/cells8101131 - 23 Sep 2019

Cited by 144 | Viewed by 8934

Abstract

Ischemia-reperfusion injury is an important cause of liver damage occurring during surgical procedures including hepatic resection and liver transplantation, and represents the main underlying cause of graft dysfunction and liver failure post-transplantation. To date, ischemia-reperfusion injury is an unsolved problem in clinical practice. [...] Read more.

Ischemia-reperfusion injury is an important cause of liver damage occurring during surgical procedures including hepatic resection and liver transplantation, and represents the main underlying cause of graft dysfunction and liver failure post-transplantation. To date, ischemia-reperfusion injury is an unsolved problem in clinical practice. In this context, inflammasome activation, recently described during ischemia-reperfusion injury, might be a potential therapeutic target to mitigate the clinical problems associated with liver transplantation and hepatic resections. The present review aims to summarize the current knowledge in inflammasome-mediated inflammation, describing the experimental models used to understand the molecular mechanisms of inflammasome in liver ischemia-reperfusion injury. In addition, a clear distinction between steatotic and non-steatotic livers and between warm and cold ischemia-reperfusion injury will be discussed. Finally, the most updated therapeutic strategies, as well as some of the scientific controversies in the field will be described. Such information may be useful to guide the design of better experimental models, as well as the effective therapeutic strategies in liver surgery and transplantation that can succeed in achieving its clinical application. Full article

(This article belongs to the Special Issue Mechanisms of Inflammasome Activation)

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23 pages, 1759 KiB

Open AccessReview

The Molecular Links between Cell Death and Inflammasome

by Kwang-Ho Lee and Tae-Bong Kang

Cells 2019, 8(9), 1057; https://doi.org/10.3390/cells8091057 - 10 Sep 2019

Cited by 44 | Viewed by 7275

Abstract

Programmed cell death pathways and inflammasome activation pathways can be genetically and functionally separated. Inflammasomes are specialized protein complexes that process pro-inflammatory cytokines, interleukin-1β (IL-1β), and IL-18 to bioactive forms for protection from a wide range of pathogens, as well as environmental and [...] Read more.

Programmed cell death pathways and inflammasome activation pathways can be genetically and functionally separated. Inflammasomes are specialized protein complexes that process pro-inflammatory cytokines, interleukin-1β (IL-1β), and IL-18 to bioactive forms for protection from a wide range of pathogens, as well as environmental and host-derived danger molecules. Programmed cell death has been extensively studied, and its role in the development, homeostasis, and control of infection and danger is widely appreciated. Apoptosis and the recently recognized necroptosis are the best-characterized forms of programmed death, and the interplay between them through death receptor signaling is also being studied. Moreover, growing evidence suggests that many of the signaling molecules known to regulate programmed cell death can also modulate inflammasome activation in a cell-intrinsic manner. Therefore, in this review, we will discuss the current knowledge concerning the role of the signaling molecules originally associated with programmed cell death in the activation of inflammasome and IL-1β processing. Full article

(This article belongs to the Special Issue Mechanisms of Inflammasome Activation)

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14 pages, 1179 KiB

Open AccessReview

Zebrafish in Inflammasome Research

by Gabriel Forn-Cuní, Annemarie H. Meijer and Monica Varela

Cells 2019, 8(8), 901; https://doi.org/10.3390/cells8080901 - 15 Aug 2019

Cited by 31 | Viewed by 6510

Abstract

Inflammasomes are cytosolic multiprotein complexes that regulate inflammatory responses to danger stimuli and infection, and their dysregulation is associated with an increasing number of autoinflammatory diseases. In recent years, zebrafish models of human pathologies to study inflammasome function in vivo have started to [...] Read more.

Inflammasomes are cytosolic multiprotein complexes that regulate inflammatory responses to danger stimuli and infection, and their dysregulation is associated with an increasing number of autoinflammatory diseases. In recent years, zebrafish models of human pathologies to study inflammasome function in vivo have started to emerge. Here, we discuss inflammasome research in zebrafish in light of current knowledge about mammalian inflammasomes. We summarize the evolutionary conservation of inflammasome components between zebrafish and mammals, highlighting the similarities and possible divergence in functions of these components. We present new insights into the evolution of the caspase-1 family in the teleost lineage, and how its evolutionary origin may help contextualize its functions. We also review existing infectious and non-infectious models in zebrafish in which inflammasomes have been directly implicated. Finally, we discuss the advantages of zebrafish larvae for intravital imaging of inflammasome activation and summarize available tools that will help to advance inflammasome research. Full article

(This article belongs to the Special Issue Mechanisms of Inflammasome Activation)

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