Sublytic membrane attack complex drives glycolysis and mitochondrial dysfunction with inflammatory consequences in human monocyte-derived macrophages

Abstract The complement system is an ancient and critical element of the innate immune system. The terminal step in the complement pathway, the membrane attack complex (MAC), has previously been linked to inflammasome activation and is linked to the pathogenesis of multiple diseases including rheumatoid arthritis and neurodegeneration. Using both metabolomic and proteomic approaches, here we show that in human monocyte-derived macrophages a sublytic concentration of MAC mediates a previously uncharacterised metabolic shift, mitochondrial dysfunction and upregulation of glycolysis-promoting genes. This skewing of metabolism coupled with mitochondrial dysfunction drives ROS-mediated NLRP3 inflammasome activation and subsequent gasdermin D activation and pro-inflammatory cytokine production and release. Together, these data elucidate a novel immunometabolic signalling cascade in MAC-stimulated human macrophages, the consequences of which have implications in considering much needed novel therapeutic options for diseases linked to aberrant complement activation

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Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis

Gut ◽

10.1136/gutjnl-2018-316670 ◽

2019 ◽

Vol 68 (8) ◽

pp. 1477-1492 ◽

Cited By ~ 28

Author(s):

Lijun Liao ◽

Kai Markus Schneider ◽

Eric J C Galvez ◽

Mick Frissen ◽

Hanns-Ulrich Marschall ◽

...

Keyword(s):

Immune Response ◽

Liver Injury ◽

Sclerosing Cholangitis ◽

Functional Role ◽

Innate Immune ◽

Caspase 8 ◽

Inflammasome Activation ◽

Intestinal Dysbiosis ◽

Nlrp3 Inflammasome Activation

ObjectiveThere is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut–liver crosstalk for CLD in the murine Mdr2 knockout (Mdr2−/−) model resembling human primary sclerosing cholangitis (PSC).DesignMale Mdr2−/−, Mdr2−/− crossed with hepatocyte-specific deletion of caspase-8 (Mdr2−/−/Casp8∆hepa) and wild-type (WT) control mice were housed for 8 or 52 weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role of Mdr2−/−-associated intestinal dysbiosis was studied by microbiota transfer experiments.ResultsMdr2−/− mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut–liver axis. Intestinal dysbiosis in Mdr2−/− mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer of Mdr2−/− microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature.ConclusionsMDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.

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Sendai Virus V Protein Inhibits the Secretion of Interleukin-1β by Preventing NLRP3 Inflammasome Assembly

Journal of Virology ◽

10.1128/jvi.00842-18 ◽

2018 ◽

Vol 92 (19) ◽

Cited By ~ 7

Author(s):

Takayuki Komatsu ◽

Yukie Tanaka ◽

Yoshinori Kitagawa ◽

Naoki Koide ◽

Yoshikazu Naiki ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Sendai Virus ◽

Nipah Virus ◽

Innate Immune ◽

Parainfluenza Virus ◽

Inflammasome Activation ◽

V Protein ◽

Nlrp3 Inflammasome Activation ◽

Human Parainfluenza Virus

ABSTRACT Inflammasomes play a key role in host innate immune responses to viral infection by caspase-1 (Casp-1) activation to facilitate interleukin-1β (IL-1β) secretion, which contributes to the host antiviral defense. The NLRP3 inflammasome consists of the cytoplasmic sensor molecule NLRP3, adaptor protein ASC, and effector protein pro-caspase-1 (pro-Casp-1). NLRP3 and ASC promote pro-Casp-1 cleavage, leading to IL-1β maturation and secretion. However, as a countermeasure, viral pathogens have evolved virulence factors to antagonize inflammasome pathways. Here we report that V gene knockout Sendai virus [SeV V(−)] induced markedly greater amounts of IL-1β than wild-type SeV in infected THP1 macrophages. Deficiency of NLRP3 in cells inhibited SeV V(−)-induced IL-1β secretion, indicating an essential role for NLRP3 in SeV V(−)-induced IL-1β activation. Moreover, SeV V protein inhibited the assembly of NLRP3 inflammasomes, including NLRP3-dependent ASC oligomerization, NLRP3-ASC association, NLRP3 self-oligomerization, and intermolecular interactions between NLRP3 molecules. Furthermore, a high correlation between the NLRP3-binding capacity of V protein and the ability to block inflammasome complex assembly was observed. Therefore, SeV V protein likely inhibits NLRP3 self-oligomerization by interacting with NLRP3 and inhibiting subsequent recruitment of ASC to block NLRP3-dependent ASC oligomerization, in turn blocking full activation of the NLRP3 inflammasome and thus blocking IL-1β secretion. Notably, the inhibitory action of SeV V protein on NLRP3 inflammasome activation is shared by other paramyxovirus V proteins, such as Nipah virus and human parainfluenza virus type 2. We thus reveal a mechanism by which paramyxovirus inhibits inflammatory responses by inhibiting NLRP3 inflammasome complex assembly and IL-1β activation. IMPORTANCE The present study demonstrates that the V protein of SeV, Nipah virus, and human parainfluenza virus type 2 interacts with NLRP3 to inhibit NLRP3 inflammasome activation, potentially suggesting a novel strategy by which viruses evade the host innate immune response. As all members of the Paramyxovirinae subfamily carry similar V genes, this new finding may also lead to identification of novel therapeutic targets for paramyxovirus infection and related diseases.

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Internalization of the Membrane Attack Complex Triggers NLRP3 Inflammasome Activation and IL-1β Secretion in Human Macrophages

Frontiers in Immunology ◽

10.3389/fimmu.2021.720655 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ines Diaz-del-Olmo ◽

Jonathan Worboys ◽

Fatima Martin-Sanchez ◽

Anna Gritsenko ◽

Ashley R. Ambrose ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Pore Formation ◽

Membrane Attack Complex ◽

Inflammasome Activation ◽

Adapter Protein ◽

Human Macrophages ◽

Danger Signals ◽

Nlrp3 Inflammasome Activation ◽

Golgi Network ◽

Stimulation Of

Interleukin 1β (IL-1β) plays a major role in inflammation and is secreted by immune cells, such as macrophages, upon recognition of danger signals. Its secretion is regulated by the inflammasome, the assembly of which results in caspase 1 activation leading to gasdermin D (GSDMD) pore formation and IL-1β release. During inflammation, danger signals also activate the complement cascade, resulting in the formation of the membrane attack complex (MAC). Here, we report that stimulation of LPS-primed human macrophages with sub-lytic levels of MAC results in activation of the NOD-like receptor 3 (NLRP3) inflammasome and GSDMD-mediated IL-1β release. The MAC is first internalized into endosomes and then colocalizes with inflammasome components; adapter protein apoptosis associated speck-like protein containing a CARD (ASC) and NLRP3. Pharmacological inhibitors established that MAC-triggered activation of the NLRP3 inflammasome was dependent on MAC endocytosis. Internalization of the MAC also caused dispersion of the trans-Golgi network. Thus, these data uncover a role for the MAC in activating the inflammasome and triggering IL-1β release in human macrophages.

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PAF and the inflammasome

Science Signaling ◽

10.1126/scisignal.aaz7370 ◽

2019 ◽

Vol 12 (602) ◽

pp. eaaz7370

Author(s):

John F. Foley

Keyword(s):

Nlrp3 Inflammasome ◽

Inflammatory Cytokine ◽

Cytokine Production ◽

Inflammasome Activation ◽

Inflammatory Cytokine Production ◽

Nlrp3 Inflammasome Activation

The phospholipid PAF stimulates NLRP3 inflammasome activation and inflammatory cytokine production independently of its GPCR.

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Impact of human monocyte and macrophage polarization on NLR expression and NLRP3 inflammasome activation

PLoS ONE ◽

10.1371/journal.pone.0175336 ◽

2017 ◽

Vol 12 (4) ◽

pp. e0175336 ◽

Cited By ~ 75

Author(s):

Fawaz Awad ◽

Eman Assrawi ◽

Claire Jumeau ◽

Sophie Georgin-Lavialle ◽

Laetitia Cobret ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Macrophage Polarization ◽

Human Monocyte ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation

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NLRP3 inflammasome activation is involved in Ang II-induced kidney damage via mitochondrial dysfunction

Oncotarget ◽

10.18632/oncotarget.11091 ◽

2016 ◽

Vol 7 (34) ◽

pp. 54290-54302 ◽

Cited By ~ 21

Author(s):

Yi Wen ◽

Yiran Liu ◽

Taotao Tang ◽

Linli Lv ◽

Hong Liu ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Nlrp3 Inflammasome ◽

Kidney Damage ◽

Inflammasome Activation ◽

Ang Ii ◽

Nlrp3 Inflammasome Activation

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NLRP3 Inflammasome in Diabetic Cardiomyopathy and Exercise Intervention

International Journal of Molecular Sciences ◽

10.3390/ijms222413228 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13228

Author(s):

Yi Sun ◽

Shuzhe Ding

Keyword(s):

Diabetic Cardiomyopathy ◽

Nlrp3 Inflammasome ◽

Exercise Intervention ◽

Inflammatory Responses ◽

Innate Immune ◽

Inflammasome Activation ◽

Low Grade ◽

Chronic Exercise ◽

Nlrp3 Inflammasome Activation ◽

Low Grade Inflammation

Diabetic cardiomyopathy (DCM), as a common complication of diabetes, is characterized by chronic low-grade inflammation. The NLRP3 inflammasome is a key sensor mediating innate immune and inflammatory responses. However, the mechanisms initiating and promoting NLRP3 inflammasome activation in DCM is largely unexplored. The aim of the present review is to describe the link between NLRP3 inflammasome and DCM, and to provide evidence highlighting the importance of exercise training in DCM intervention. Collectively, this evidence suggests that DCM is an inflammatory disease aggravated by NLRP3 inflammasome-mediated release of IL-1β and IL-18. In addition, chronic exercise intervention is an effective preventive and therapeutic method to alleviate DCM via modulating the NLRP3 inflammasome.

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The Role of Inflammasome Activation in Early HIV Infection

Journal of Immunology Research ◽

10.1155/2021/1487287 ◽

2021 ◽

Vol 2021 ◽

pp. 1-7

Author(s):

Cyril Jabea Ekabe ◽

Njinju Asaba Clinton ◽

Jules Kehbila ◽

Ngangom Chouamo Franck

Keyword(s):

Acute Inflammation ◽

Vital Role ◽

Innate Immune ◽

Target Cells ◽

Inflammasome Activation ◽

Virus Infections ◽

Hiv Transcription ◽

Nlrp3 Inflammasome Activation ◽

Hiv Entry

The inflammasome pathway is an important arm of the innate immune system that provides antiviral immunity against many viruses. The main pathways involved in virus infections include the NLRP3, IFI16, and AIM2 pathways. However, a succinct understanding of its role in HIV is not yet well elucidated. In this review, we showed that NLRP3 inflammasome activation plays a vital role in inhibiting HIV entry into target cells via the purinergic pathway; IFI16 detects intracellular HIV ssDNA, triggers interferon I and III production, and inhibits HIV transcription; and AIM2 binds to HIV dsDNA and triggers acute inflammation and pyroptosis. Remarkably, by understanding these mechanisms, new therapeutic strategies can be developed against the disease.

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Increasing Autophagy ameliorate all-trans-retinal-activated NLRP3 Inflammasome 2 in human THP-1 macrophage cells

10.21203/rs.3.rs-797831/v1 ◽

2021 ◽

Author(s):

Qingqing Xia ◽

Lvxing Huang ◽

Hengyi Chen ◽

Yingying Zhou ◽

Lingmin Zhang ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Underlying Mechanism ◽

Innate Immune ◽

Cell Counting ◽

Autophagic Flux ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation ◽

Related Proteins ◽

Excessive Activation ◽

Insight Into

Abstract BackgroundProfound inflammation that mediated by innate immune sensors can be observed in retina, and is considered to play an important role in the pathogenesis of all-trans-retinal (atRAL)-caused retinal degeneration. However, the underlying mechanism remains elusive. MethodsCell viability was detected with Cell Counting Kit-8 (CCK-8). The concentration of IL-1β was evaluated using IL-1β ELISA Kits. The levels of autophagy-related proteins were measured by Western blotting. The measurement of autophagic flux was performed with virus vectors packing tandem monomeric mCherry-eGFP-tagged LC3B. ResultsWe focused on studying the effects of atRAL on macrophage cell line THP-1 and determining the underlying signal pathway through pharmacological and genetical manipulation. We first found the maturation and release of IL-1β was regulated by the activation of NLRP3 inflammasome. We secondly found that mitochondria-associated reactive oxygen species (ROS) were involved in the regulation of NLRP3 inflammasome activation and caspase 1 cleavage. Finally, we found that atRAL functionally activated autophagy in THP-1 cells, and atRAL-caused NLRP3 inflammasome activation is suppressed by autophagy. Overall, our results show atRAL simultaneously activates NLRP3 inflammasome and autophagy in THP-1 cells, and increasing autophagy leads to the inhibition of the excessive activation of NLRP3 inflammasome. Our study provides new insight into the pathogenesis of aging related retina degeneration.

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