Role of the NLRP3 inflammasome in autoimmune diseases

Li, Zhe; Guo, Jialong; Bi, Liqi

doi:10.1016/j.biopha.2020.110542

Cited by 164 publications

(109 citation statements)

References 170 publications

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“…The Nlrp3 inflammasome is also involved in certain other hematological pathologies, including i) myelodysplastic syndrome, ii) myeloproliferative neoplasms, iii) leukemia, iv) graft-versushost disease (GvHD) after transplantation, and v) cytokine storms as a complication of CAR-T cell therapy or COVID19 infection (24,28,(33)(34)(35)(36)(37)(38)(39). The pleiotropic role of Nlrp3 inflammasome in hematopoiesis has been a subject of several excellent reviews (40)(41)(42)(43)(44)(45)(46). In this review, however, we will focus on the "good side" of the Nlrp3 inflammasome as a new positive regulator of stem cell trafficking and homeostasis of the BM microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Extracellular Adenosine Triphosphate (eATP) and Its Metabolite, Extracellular Adenosine (eAdo), as Opposing “Yin–Yang” Regulators of Nlrp3 Inflammasome in the Trafficking of Hematopoietic Stem/Progenitor Cells

Ratajczak

Kucia

2021

Front. Immunol.

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Nlrp3 inflammasome plays a pleiotropic role in hematopoietic cells. On the one hand, physiological activation of this intracellular protein complex is crucial to maintaining normal hematopoiesis and the trafficking of hematopoietic stem progenitor cells (HSPCs). On the other hand, its hyperactivation may lead to cell death by pyroptosis, and prolonged activity is associated with sterile inflammation of the BM and, as a consequence, with the HSPCs aging and origination of myelodysplasia and leukemia. Thus, we need to understand better this protein complex’s actions to define the boundaries of its safety window and study the transition from being beneficial to being detrimental. As demonstrated, the Nlrp3 inflammasome is expressed and active both in HSPCs and in the non-hematopoietic cells that are constituents of the bone marrow (BM) microenvironment. Importantly, the Nlrp3 inflammasome responds to mediators of purinergic signaling, and while extracellular adenosine triphosphate (eATP) activates this protein complex, its metabolite extracellular adenosine (eAdo) has the opposite effect. In this review, we will discuss and focus on the physiological consequences of the balance between eATP and eAdo in regulating the trafficking of HSPCs in an Nlrp3 inflammasome-dependent manner, as seen during pharmacological mobilization from BM into peripheral blood (PB) and in the reverse mechanism of homing from PB to BM and engraftment. We propose that both mediators of purinergic signaling and the Nlrp3 inflammasome itself may become important therapeutic targets in optimizing the trafficking of HSPCs in clinical settings.

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Section: Introductionmentioning

confidence: 99%

Extracellular Adenosine Triphosphate (eATP) and Its Metabolite, Extracellular Adenosine (eAdo), as Opposing “Yin–Yang” Regulators of Nlrp3 Inflammasome in the Trafficking of Hematopoietic Stem/Progenitor Cells

Ratajczak

Kucia

2021

Front. Immunol.

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“…In this direction, researchers have identified the DCs from Nlrp3-/-and Caspase 1-/mice to exhibit reduced levels of DNA damage and p53-induced apoptosis as a result of effective DNA repair mechanisms, following exposure to DNA-damaging agents such as oxidative H 2 O 2 and genotoxic MSU crystals [71]. Of note, high expression levels of Nlrp3 and Caspase 1 have been associated with a plethora of autoimmune diseases [72,73]. Therefore, these data imply that the DCs may require decreased Nlrp3 and Caspase 1 expression levels to have an efficient DDR, yet many autoimmune patients are characterized by increased levels and, accordingly, they may undergo a defective DDR.…”

Section: Aberrant Ddr In Innate Cells May Exacerbate Aberrant Immune Responses In Adaptive Cells: the Case Of Dendritic Cells (Dcs)mentioning

confidence: 99%

DNA Damage Response in the Adaptive Arm of the Immune System: Implications for Autoimmunity

Manolakou

Verginis

Boumpas

2021

IJMS

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In complex environments, cells have developed molecular responses to confront threats against the genome and achieve the maintenance of genomic stability assuring the transfer of undamaged DNA to their progeny. DNA damage response (DDR) mechanisms may be activated upon genotoxic or environmental agents, such as cytotoxic drugs or ultraviolet (UV) light, and during physiological processes requiring DNA transactions, to restore DNA alterations that may cause cellular malfunction and affect viability. In addition to the DDR, multicellular organisms have evolved specialized immune cells to respond and defend against infections. Both adaptive and innate immune cells are subjected to DDR processes, either as a prerequisite to the immune response, or as a result of random endogenous and exogenous insults. Aberrant DDR activities have been extensively studied in the immune cells of the innate arm, but not in adaptive immune cells. Here, we discuss how the aberrant DDR may lead to autoimmunity, with emphasis on the adaptive immune cells and the potential of therapeutic targeting.

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“…Similarly to MG patients, experimental autoimmune MG (EAMG) mouse models show weakness in the skeletal muscles over time potentially, partly caused by the translocation of the neuronal NO synthase from the muscle membrane to the cytoplasm, due to blocked neuromuscular transmission [ 225 ]. Due to the suspected involvement of the NLRP3 inflammasome in autoimmune diseases [ 226 ], researchers were interested in investigating its role in MG. Overall, a caspase-1 inhibitor significantly ameliorated the symptoms of the disease in a EAMG rat model [ 227 ].…”

Section: Other Rare Neuromuscular Diseasesmentioning

confidence: 99%

Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

Péladeau

Sandhu

2021

IJMS

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Inflammasomes are molecular hubs that are assembled and activated by a host in response to various microbial and non-microbial stimuli and play a pivotal role in maintaining tissue homeostasis. The NLRP3 is a highly promiscuous inflammasome that is activated by a wide variety of sterile triggers, including misfolded protein aggregates, and drives chronic inflammation via caspase-1-mediated proteolytic cleavage and secretion of proinflammatory cytokines, interleukin-1β and interleukin-18. These cytokines further amplify inflammatory responses by activating various signaling cascades, leading to the recruitment of immune cells and overproduction of proinflammatory cytokines and chemokines, resulting in a vicious cycle of chronic inflammation and tissue damage. Neuromuscular diseases are a heterogeneous group of muscle disorders that involve injury or dysfunction of peripheral nerves, neuromuscular junctions and muscles. A growing body of evidence suggests that dysregulation, impairment or aberrant NLRP3 inflammasome signaling leads to the initiation and exacerbation of pathological processes associated with neuromuscular diseases. In this review, we summarize the available knowledge about the NLRP3 inflammasome in neuromuscular diseases that affect the peripheral nervous system and amyotrophic lateral sclerosis, which affects the central nervous system. In addition, we also examine whether therapeutic targeting of the NLRP3 inflammasome components is a viable approach to alleviating the detrimental phenotype of neuromuscular diseases and improving clinical outcomes.

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Role of the NLRP3 inflammasome in autoimmune diseases

Cited by 164 publications

References 170 publications

Extracellular Adenosine Triphosphate (eATP) and Its Metabolite, Extracellular Adenosine (eAdo), as Opposing “Yin–Yang” Regulators of Nlrp3 Inflammasome in the Trafficking of Hematopoietic Stem/Progenitor Cells

Extracellular Adenosine Triphosphate (eATP) and Its Metabolite, Extracellular Adenosine (eAdo), as Opposing “Yin–Yang” Regulators of Nlrp3 Inflammasome in the Trafficking of Hematopoietic Stem/Progenitor Cells

DNA Damage Response in the Adaptive Arm of the Immune System: Implications for Autoimmunity

Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

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