The NLRP3 Inflammasome and Its Role in Sepsis Development

Danielski, Lucinéia Gainski; Giustina, Amanda Della; Bonfante, Sandra; Barichello, Tatiana; Petronilho, Fabrícia

doi:10.1007/s10753-019-01124-9

Cited by 184 publications

(115 citation statements)

References 64 publications

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“…BTK is also involved in the activation of the toll-like receptor (TLR) signaling pathways (by binding to the TIR domain of TLR4 and TLR's adaptor molecules MyD88, and Mal) and the NLRP3 inflammasome (by binding to the ASC component) ( 7 – 9 ). Activation of both the TLR signaling pathway and the NLRP3 inflammasome play a pivotal role in the pathophysiology of sepsis ( 10 , 11 ). The expression of BTK is not restricted to B cells, as BTK is also expressed in cells of myeloid lineage, including macrophages and neutrophils ( 12 , 13 ), activation of which contributes to the pathophysiology of sepsis.…”

Section: Introductionmentioning

confidence: 99%

X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure

et al. 2020

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We previously reported the Bruton's tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib improve outcomes in a mouse model of polymicrobial sepsis. Now we show that genetic deficiency of the BTK gene alone in Xid mice confers protection against cardiac, renal, and liver injury in polymicrobial sepsis and reduces hyperimmune stimulation (“cytokine storm”) induced by an overwhelming bacterial infection. Protection is due in part to enhanced bacterial phagocytosis in vivo , changes in lipid metabolism and decreased activation of NF-κB and the NLRP3 inflammasome. The inactivation of BTK leads to reduced innate immune cell recruitment and a phenotypic switch from M1 to M2 macrophages, aiding in the resolution of sepsis. We have also found that BTK expression in humans is increased in the blood of septic non-survivors, while lower expression is associated with survival from sepsis. Importantly no further reduction in organ damage, cytokine production, or changes in plasma metabolites is seen in Xid mice treated with the BTK inhibitor ibrutinib, demonstrating that the protective effects of BTK inhibitors in polymicrobial sepsis are mediated solely by inhibition of BTK and not by off-target effects of this class of drugs.

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Section: Introductionmentioning

confidence: 99%

X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure

et al. 2020

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“…However, the present study showed that posttreatment of Maresin1 did not affect the level of LPS-induced TNF-α, implying that Maresin1 inhibited the second signal of NLRP3 inflammasome activation. Furthermore, previous studies have reported that Maresin1 has an effect on other diseases associated with NLRP3 inflammasome, including atherosclerosis, and insulin resistance is observed, 32,33 suggesting that Maresin1 exerts its protective effects against these diseases via not only previously proposed mechanisms, but also through the inhibition of the NLRP3 inflammasome. However, further studies are required to confirm this hypothesis.…”

Section: Discussionmentioning

confidence: 93%

“…Increasing evidence suggests that NLRP3 inflammasome can produce pro-inflammatory cytokines and is implicated the development of sepsis. 33,34 This study assessed whether Maresin1 could suppress the inflammatory responses by inhibiting NLRP3 inflammasome activation in septic shock. The WT or Nlrp3 ko mice were treated with Maresin1 when challenged with LPS to induce septic shock.…”

Section: Lps-induced Sepsis Via Inhibition Of Nlrp3 Inflammasomementioning

confidence: 99%

Posttreatment of Maresin1 Inhibits NLRP3 inflammasome activation via promotion of NLRP3 ubiquitination

Zheng

et al. 2020

FASEB j.

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Maresin1 is a potent lipid mediator exhibiting potential anti‐inflammatory activity in a variety of inflammatory diseases, however, the underlying mechanisms remain poorly understood. Excessive activation of NLRP3 inflammasome has been established in multiple inflammatory diseases. Here, we show that Maresin1 dose‐dependently inhibited the NLRP3 inflammasome activation and subsequent caspase‐1 activation and IL‐1β secretion. This inhibitory effect could be reversed by KH7 and H89, the inhibitors of the cAMP‐PKA signaling pathway. Activation of PKA kinase induced by Maresin1 led to the K63‐linked ubiquitination of NLRP3 in macrophages. Maresin1 attenuated serum IL‐1β secretion through inhibition of NLRP3 inflammasome in vivo using Nlrp3‐deficient mouse models of lipopolysaccharide (LPS)‐induced sepsis. Maresin1 also repressed MSU‐induced peritonitis. This study suggests that Maresin1 is an inhibitor of NLRP3 inflammasome activation and can be used clinically in the treatment of NLRP3 inflammasome‐driven inflammatory diseases.

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“…Thus, mitochondria of innate immune cells provide a signaling center [223] for their specific germline-encoded immune receptors, termed pattern-recognition receptors. Several classes are distinguished, such as toll-like receptors (TLRs) [224]; NOD-like receptors (NLR, e.g., NLRP3, i.e., NOD-like receptor containing pyrin domain 3), forming large cytosolic protein complexes, inflammasomes [225,226]; C-type lectin receptors (CLR), recognizing microorganisms and tumor cells [227]; and RIG-like receptors as sensors of nucleic acids [228], which also include cyclic guanosine monophosphate-adenosine monophosphate (cGAS) [229].…”

Section: Mitochondrial Role and Signaling In Innate Immune Cellsmentioning

confidence: 99%

Redox Signaling from Mitochondria: Signal Propagation and Its Targets

2020

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Progress in mass spectroscopy of posttranslational oxidative modifications has enabled researchers to experimentally verify the concept of redox signaling. We focus here on redox signaling originating from mitochondria under physiological situations, discussing mechanisms of transient redox burst in mitochondria, as well as the possible ways to transfer such redox signals to specific extramitochondrial targets. A role of peroxiredoxins is described which enables redox relay to other targets. Examples of mitochondrial redox signaling are discussed: initiation of hypoxia-inducible factor (HIF) responses; retrograde redox signaling to PGC1α during exercise in skeletal muscle; redox signaling in innate immune cells; redox stimulation of insulin secretion, and other physiological situations.

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The NLRP3 Inflammasome and Its Role in Sepsis Development

Cited by 184 publications

References 64 publications

X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure

X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure

Posttreatment of Maresin1 Inhibits NLRP3 inflammasome activation via promotion of NLRP3 ubiquitination

Redox Signaling from Mitochondria: Signal Propagation and Its Targets

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