Walking down Skeletal Muscle Lane: From Inflammasome to Disease

Over the last decade, innate immune system receptors and sensors called inflammasomes have been identified to play key pathological roles in the development and progression of numerous diseases. Among them, the nucleotide-binding oligomerization domain (NOD-), leucine-rich repeat (LRR-) and pyrin domain-containing protein 3 (NLRP3) inflammasome is probably the best characterized. To date, NLRP3 has been extensively studied in the heart, where its effects and actions have been broadly documented in numerous cardiovascular diseases. However, little is still known about NLRP3 implications in muscle disorders affecting non-cardiac muscles. In this review, we summarize and present the current knowledge regarding the function of NLRP3 in diseased skeletal muscle, and discuss the potential therapeutic options targeting the NLRP3 inflammasome in muscle disorders.

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The NLRP3 Inflammasome and Its Role in the Pathogenicity of Leukemia

International Journal of Molecular Sciences ◽

10.3390/ijms22031271 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1271

Author(s):

Laura Urwanisch ◽

Michela Luciano ◽

Jutta Horejs-Hoeck

Keyword(s):

Nlrp3 Inflammasome ◽

Innate Immune System ◽

Inflammatory Cell ◽

Current Knowledge ◽

Innate Immune ◽

Leukemic Cells ◽

Different Types ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

Chronic inflammation contributes to the development and progression of various tumors. Especially where the inflammation is mediated by cells of the innate immune system, the NLRP3 inflammasome plays an important role, as it senses and responds to a variety of exogenous and endogenous pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). The NLRP3 inflammasome is responsible for the maturation and secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 and for the induction of a type of inflammatory cell death known as pyroptosis. Overactivation of the NLRP3 inflammasome can be a driver of various diseases. Since leukemia is known to be an inflammation-driven cancer and IL-1β is produced in elevated levels by leukemic cells, research on NLRP3 in the context of leukemia has increased in recent years. In this review, we summarize the current knowledge on leukemia-promoting inflammation and, in particular, the role of the NLRP3 inflammasome in different types of leukemia. Furthermore, we examine a connection between NLRP3, autophagy and leukemia.

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The Roles of the NLRP3 Inflammasome in Neurodegenerative and Metabolic Diseases and in Relevant Advanced Therapeutic Interventions

Genes ◽

10.3390/genes11020131 ◽

2020 ◽

Vol 11 (2) ◽

pp. 131 ◽

Cited By ~ 11

Author(s):

Rameez Hassan Pirzada ◽

Nasir Javaid ◽

Sangdun Choi

Keyword(s):

Nlrp3 Inflammasome ◽

Metabolic Diseases ◽

Drug Research ◽

Innate Immune ◽

Therapeutic Interventions ◽

Interleukin 18 ◽

Pyrin Domain ◽

Nlrp3 Inflammasomes ◽

Oligomerization Domain

Inflammasomes are intracellular multiprotein complexes in the cytoplasm that regulate inflammation activation in the innate immune system in response to pathogens and to host self-derived molecules. Recent advances greatly improved our understanding of the activation of nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasomes at the molecular level. The NLRP3 belongs to the subfamily of NLRP which activates caspase 1, thus causing the production of proinflammatory cytokines (interleukin 1β and interleukin 18) and pyroptosis. This inflammasome is involved in multiple neurodegenerative and metabolic disorders including Alzheimer’s disease, multiple sclerosis, type 2 diabetes mellitus, and gout. Therefore, therapeutic targeting to the NLRP3 inflammasome complex is a promising way to treat these diseases. Recent research advances paved the way toward drug research and development using a variety of machine learning-based and artificial intelligence-based approaches. These state-of-the-art approaches will lead to the discovery of better drugs after the training of such a system.

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Exosomes Regulate NLRP3 Inflammasome in Diseases

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.802509 ◽

2022 ◽

Vol 9 ◽

Author(s):

Zhangwang Li ◽

Xinyue Chen ◽

Junjie Tao ◽

Ao Shi ◽

Jing Zhang ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Critical Role ◽

Disease Process ◽

Diagnostic Tools ◽

Signal Molecules ◽

Leucine Rich Repeat ◽

Pyrin Domain ◽

Repeat Domain ◽

Oligomerization Domain

Emerging evidence has suggested the unique and critical role of exosomes as signal molecules vector in various diseases. Numerous researchers have been trying to identify how these exosomes function in immune progression, as this could promote their use as biomarkers for the disease process and potential promising diagnostic tools. NOD-like receptor (NLR) family, pyrin domain containing 3 (NLRP3), a tripartite protein, contains three functional domains a central nucleotide-binding and oligomerization domain (NACHT), an N-terminal pyrin domain (PYD), and a leucine-rich repeat domain (LRR). Of note, existing studies have identified exosome as a novel mediator of the NLRP3 inflammasome, which is critical in diseases progression. However, the actual mechanisms and clinical treatment related to exosomes and NLRP3 are still not fully understood. Herein, we presented an up-to-date review of exosomes and NLRP3 in diseases, outlining what is known about the role of exosomes in the activation of NLRP3 inflammasome and also highlighting areas of this topic that warrant further study.

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NLRP3 Inflammasome in the Pathophysiology of Hemorrhagic Stroke: A Review

Current Neuropharmacology ◽

10.2174/1570159x17666181227170053 ◽

2019 ◽

Vol 17 (7) ◽

pp. 582-589 ◽

Cited By ~ 10

Author(s):

Yujie Luo ◽

Cesar Reis ◽

Sheng Chen

Keyword(s):

Immune System ◽

Brain Injury ◽

Nlrp3 Inflammasome ◽

Innate Immune System ◽

Hemorrhagic Stroke ◽

Innate Immune ◽

High Morbidity ◽

Pyrin Domain ◽

Cytokines And Chemokines

Hemorrhagic stroke is a devastating disease with high morbidity and mortality. There is still a lack of effective therapeutic approach. The recent studies have shown that the innate immune system plays a significant role in hemorrhagic stroke. Microglia, as major components in innate immune system, are activated and then can release cytokines and chemokines in response to hemorrhagic stroke, and ultimately led to neuroinflammation and brain injury. The NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome is predominantly released by microglia and is believed as the main contributor of neuroinflammation. Several studies have focused on the role of NLRP3 inflammasome in hemorrhagic stroke-induced brain injury, however, the specific mechanism of NLRP3 activation and regulation remains unclear. This review summarized the mechanism of NLRP3 activation and its role in hemorrhagic stroke and discussed the translational significance.

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NOD-Like Receptors: Guards of Cellular Homeostasis Perturbation during Infection

International Journal of Molecular Sciences ◽

10.3390/ijms22136714 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6714

Author(s):

Gang Pei ◽

Anca Dorhoi

Keyword(s):

Immune System ◽

Innate Immune System ◽

Current Knowledge ◽

Protein Translation ◽

Innate Immune ◽

Cellular Homeostasis ◽

Translation Block ◽

Cytoskeleton Disruption ◽

Molecular Patterns ◽

Fine Tune

The innate immune system relies on families of pattern recognition receptors (PRRs) that detect distinct conserved molecular motifs from microbes to initiate antimicrobial responses. Activation of PRRs triggers a series of signaling cascades, leading to the release of pro-inflammatory cytokines, chemokines and antimicrobials, thereby contributing to the early host defense against microbes and regulating adaptive immunity. Additionally, PRRs can detect perturbation of cellular homeostasis caused by pathogens and fine-tune the immune responses. Among PRRs, nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) have attracted particular interest in the context of cellular stress-induced inflammation during infection. Recently, mechanistic insights into the monitoring of cellular homeostasis perturbation by NLRs have been provided. We summarize the current knowledge about the disruption of cellular homeostasis by pathogens and focus on NLRs as innate immune sensors for its detection. We highlight the mechanisms employed by various pathogens to elicit cytoskeleton disruption, organelle stress as well as protein translation block, point out exemplary NLRs that guard cellular homeostasis during infection and introduce the concept of stress-associated molecular patterns (SAMPs). We postulate that integration of information about microbial patterns, danger signals, and SAMPs enables the innate immune system with adequate plasticity and precision in elaborating responses to microbes of variable virulence.

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ER-Mitochondria Communication in Cells of the Innate Immune System

Cells ◽

10.3390/cells8091088 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1088 ◽

Cited By ~ 14

Author(s):

Dmitry Namgaladze ◽

Vera Khodzhaeva ◽

Bernhard Brüne

Keyword(s):

Immune System ◽

Stress Responses ◽

Innate Immune System ◽

Current Knowledge ◽

Apoptotic Cell ◽

Innate Immune ◽

Material Transfer ◽

Membrane Contact Sites ◽

Cell Type Specific ◽

In Cells

In cells the interorganelle communication comprises vesicular and non-vesicular mechanisms. Non-vesicular material transfer predominantly takes place at regions of close organelle apposition termed membrane contact sites and is facilitated by a growing number of specialized proteins. Contacts of the endoplasmic reticulum (ER) and mitochondria are now recognized to be essential for diverse biological processes such as calcium homeostasis, phospholipid biosynthesis, apoptosis, and autophagy. In addition to these universal roles, ER-mitochondria communication serves also cell type-specific functions. In this review, we summarize the current knowledge on ER-mitochondria contacts in cells of the innate immune system, especially in macrophages. We discuss ER- mitochondria communication in the context of macrophage fatty acid metabolism linked to inflammatory and ER stress responses, its roles in apoptotic cell engulfment, activation of the inflammasome, and antiviral defense.

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Protective effect of exogenous hydrogen sulfide on diaphragm muscle fibrosis in streptozotocin-induced diabetic rats

Experimental Biology and Medicine ◽

10.1177/1535370220931038 ◽

2020 ◽

Vol 245 (14) ◽

pp. 1280-1289

Author(s):

Rui Yang ◽

Qiang Jia ◽

Yan Li ◽

Shomaila Mehmood

Keyword(s):

Diabetes Mellitus ◽

Skeletal Muscle ◽

Hydrogen Sulfide ◽

Nlrp3 Inflammasome ◽

Respiratory Function ◽

Diaphragm Muscle ◽

Receptor Protein ◽

Muscle Fibrosis ◽

First Time ◽

Oligomerization Domain

Diabetes mellitus has been shown to impair respiratory function. The diaphragm is an important skeletal muscle involved in respiration. Hydrogen sulfide (H2S) is one of the three endogenous gas messengers in mammals, which exhibits anti-fibrotic activity in some types of diabetes-related complications. However, whether and how H2S exerts its anti-fibrotic activity on the diabetic diaphragmatic muscle remains unclear. In this study, we explored the anti-fibrotic activity of exogenous H2S on the diaphragm using a streptozotocin (STZ)-induced diabetic rat model. The results showed that diaphragmatic biomechanical parameters were decreased, whereas the levels of inflammatory cytokines, collagen, and nucleotide-binding oligomerization domain-like receptor protein (NLRP) 3 inflammasome-related protein expression were increased in diabetic diaphragms. This implies that diabetes causes fibrosis of the diaphragm muscle through activation of NLRP3 inflammasome. After supplementation with exogenous H2S, the diaphragmatic biomechanical and pathological alterations were ameliorated and activation of NLRP3 inflammasome was inhibited, followed by a decline in diaphragm muscle inflammation and fibrosis. These results demonstrate for the first time that exogenous H2S effectively attenuates STZ-induced diabetic diaphragm muscle fibrosis, and that the underlying mechanism may be associated with suppression of the NLRP3 inflammasome-mediated inflammatory reaction. Impact statement Diabetes mellitus is a group of chronic metabolic disorders, which causes serious damage to a variety of organs, such as the retina, heart, and skeletal muscle. The diaphragm is an important skeletal muscle involved in respiration in mammals. Fibrosis of the diaphragm muscle affects its contractility, which in turn impairs respiratory function. Accumulating evidence suggests that exogenous hydrogen sulfide (H2S) exhibits anti-fibrotic activity in diabetes mellitus, but whether and how H2S exerts this anti-fibrotic effect in the diabetic diaphragm remains unclear. The current work for the first time reveals that exogenous H2S attenuates hyperglycemia-induced fibrosis of the diaphragm muscle and strengthens diaphragmatic biomechanical properties in diabetes mellitus, and the mechanism may involve the alleviation of collagen deposition by suppression of the nucleotide-binding oligomerization domain-like receptor protein (NLRP) 3 inflammasome-mediated inflammatory reaction. Therefore, H2S supplementation could be used as an efficient targeted therapy against the NLRP3 inflammasome in the diabetic diaphragm.

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Glucocorticoids sensitize the innate immune system through regulation of the NLRP3 inflammasome.

Journal of Biological Chemistry ◽

10.1074/jbc.a111.275370 ◽

2012 ◽

Vol 287 (17) ◽

pp. 13559-13559 ◽

Cited By ~ 1

Author(s):

John M. Busillo ◽

Kathleen M. Azzam ◽

John A. Cidlowski

Keyword(s):

Immune System ◽

Nlrp3 Inflammasome ◽

Innate Immune System ◽

Innate Immune

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Neutrophils—From Bone Marrow to First-Line Defense of the Innate Immune System

Frontiers in Immunology ◽

10.3389/fimmu.2021.767175 ◽

2021 ◽

Vol 12 ◽

Author(s):

Richard Felix Kraus ◽

Michael Andreas Gruber

Keyword(s):

Immune System ◽

Innate Immune System ◽

Current Knowledge ◽

Immune Defense ◽

Innate Immune ◽

Human Organism ◽

Polymorphonuclear Cells ◽

Target Tissue ◽

First Line

Neutrophils (polymorphonuclear cells; PMNs) form a first line of defense against pathogens and are therefore an important component of the innate immune response. As a result of poorly controlled activation, however, PMNs can also mediate tissue damage in numerous diseases, often by increasing tissue inflammation and injury. According to current knowledge, PMNs are not only part of the pathogenesis of infectious and autoimmune diseases but also of conditions with disturbed tissue homeostasis such as trauma and shock. Scientific advances in the past two decades have changed the role of neutrophils from that of solely immune defense cells to cells that are responsible for the general integrity of the body, even in the absence of pathogens. To better understand PMN function in the human organism, our review outlines the role of PMNs within the innate immune system. This review provides an overview of the migration of PMNs from the vascular compartment to the target tissue as well as their chemotactic processes and illuminates crucial neutrophil immune properties at the site of the lesion. The review is focused on the formation of chemotactic gradients in interaction with the extracellular matrix (ECM) and the influence of the ECM on PMN function. In addition, our review summarizes current knowledge about the phenomenon of bidirectional and reverse PMN migration, neutrophil microtubules, and the microtubule organizing center in PMN migration. As a conclusive feature, we review and discuss new findings about neutrophil behavior in cancer environment and tumor tissue.

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