Dysregulated NLRP3 inflammasome activity results in uncontrolled inflammation, which underlies many chronic diseases. Although mitochondrial damage is needed for the assembly and activation of the ...NLRP3 inflammasome, it is unclear how macrophages are able to respond to structurally diverse inflammasome-activating stimuli. Here we show that the synthesis of mitochondrial DNA (mtDNA), induced after the engagement of Toll-like receptors, is crucial for NLRP3 signalling. Toll-like receptors signal via the MyD88 and TRIF adaptors to trigger IRF1-dependent transcription of CMPK2, a rate-limiting enzyme that supplies deoxyribonucleotides for mtDNA synthesis. CMPK2-dependent mtDNA synthesis is necessary for the production of oxidized mtDNA fragments after exposure to NLRP3 activators. Cytosolic oxidized mtDNA associates with the NLRP3 inflammasome complex and is required for its activation. The dependence on CMPK2 catalytic activity provides opportunities for more effective control of NLRP3 inflammasome-associated diseases.
Liver cell death has an essential role in nonalcoholic steatohepatitis (NASH). The activity of the energy sensor adenosine monophosphate (AMP)-activated protein kinase (AMPK) is repressed in NASH. ...Liver-specific AMPK knockout aggravated liver damage in mouse NASH models. AMPK phosphorylated proapoptotic caspase-6 protein to inhibit its activation, keeping hepatocyte apoptosis in check. Suppression of AMPK activity relieved this inhibition, rendering caspase-6 activated in human and mouse NASH. AMPK activation or caspase-6 inhibition, even after the onset of NASH, improved liver damage and fibrosis. Once phosphorylation was decreased, caspase-6 was activated by caspase-3 or -7. Active caspase-6 cleaved Bid to induce cytochrome c release, generating a feedforward loop that leads to hepatocyte death. Thus, the AMPK-caspase-6 axis regulates liver damage in NASH, implicating AMPK and caspase-6 as therapeutic targets.
Nearly two decades after the initial cloning and identification of the founding father of the tumor necrosis factor receptor (TNFR) family, much has been learned about the mechanisms by which these ...receptors signal to critical transcription factors and other targets that regulate gene expression and cellular physiology. Mitogen-activated protein kinases (MAPKs) and inhibitor of nuclear factor (NF)-κB (IκB) kinases (IKKs) were identified early on as the upstream kinases responsible for activation of activator-protein 1 (AP-1) and NF-κB, respectively, and later on for their ability to control life-or-death decisions in TNF-stimulated cells. Both of these critical pathways are regulated at the level of MAPK kinase kinases (MAP3Ks), after which point they diverge. Recent work, however, illustrates that protein ubiquitination cascades play a critical initiating role in TNFR signaling and account for spatial and temporal separation of IKK and MAPK signaling cascades and thereby determine biological specificity and outcome. Cellular inhibitors of apoptosis (cIAPs) 1 and 2 are ubiquitin (Ub) ligases (E3s) that mediate canonical Lys48-linked ubiquitination of TNFR-associated factor 3 (TRAF3), marking it for subsequent degradation by the proteasome. TRAF3 degradation releases the brake on TRAF2/6:MAP3K signaling complexes responsible for MAPK activation, leading to their translocation from the cytoplasmic segment of the receptor to the cytosol where they initiate MAPK phosphorylation and activation. By contrast, IKK activation proceeds considerably faster than MAPK activation, takes place at the receptor, and is independent of cIAP1/2 activity and TRAF3 degradation. This arrangement may be important for ensuring the proper delivery of NF-κB-dependent survival signals and conversion of JNK-promoted death signals to proliferative ones.
Tumour necrosis factor receptor (TNFR)-associated factor (TRAF) proteins are essential components of signalling pathways activated by TNFR or Toll-like receptor (TLR) family members. Acting alone or ...in combination, the seven known TRAFs control many biological processes, including cytokine production and cell survival. The function of one TRAF in particular, TRAF3, remained elusive for many years. Recent work has revealed that TRAF3 is a highly versatile regulator that positively controls type I interferon production, but negatively regulates mitogen-activated protein kinase activation and alternative nuclear factor-κB signalling. In this Review, we discuss our current understanding of the role of TRAF3 in TNFR and TLR signalling pathways, and its role in disease.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Although there are associations among oxidative stress, reduced nicotinamide adenine dinucleotide phosphate oxidase (NOX) activation, and hepatocellular carcinoma (HCC) development, it is not clear ...how NOX contributes to hepatocarcinogenesis. We studied the functions of different NOX proteins in mice after administration of a liver carcinogen.
Fourteen-day-old Nox1–/– mice, Nox4–/– mice, Nox1–/–Nox4–/– (double-knockout) mice, and wild-type (WT) C57BL/6 mice were given a single intraperitoneal injection of diethylnitrosamine (DEN) and liver tumors were examined at 9 months. We also studied the effects of DEN in mice with disruption of Nox1 specifically in hepatocytes (Nox1ΔHep), hepatic stellate cells (Nox1ΔHep), or macrophages (Nox1ΔMac). Some mice were also given injections of the NOX1-specific inhibitor ML171. To study the acute effects of DEN, 8–12-week-old mice were given a single intraperitoneal injection, and liver and serum were collected at 72 hours. Liver tissues were analyzed by histologic examination, quantitative polymerase chain reaction, and immunoblots. Hepatocytes and macrophages were isolated from WT and knockout mice and analyzed by immunoblots.
Nox4–/– mice and WT mice developed liver tumors within 9 months after administration of DEN, whereas Nox1–/– mice developed 80% fewer tumors, which were 50% smaller than those of WT mice. Nox1ΔHep and Nox1ΔHSC mice developed liver tumors of the same number and size as WT mice, whereas Nox1ΔMac developed fewer and smaller tumors, similar to Nox1–/– mice. After DEN injection, levels of tumor necrosis factor, interleukin 6 (IL6), and phosphorylated signal transducer and activator of transcription 3 were increased in livers from WT, but not Nox1–/– or Nox1ΔMac, mice. Conditioned medium from necrotic hepatocytes induced expression of NOX1 in cultured macrophages, followed by expression of tumor necrosis factor, IL6, and other inflammatory cytokines; this medium did not induce expression of IL6 or cytokines in Nox1ΔMac macrophages. WT mice given DEN followed by ML171 developed fewer and smaller liver tumors than mice given DEN followed by vehicle.
In mice given injections of a liver carcinogen (DEN), expression of NOX1 by macrophages promotes hepatic tumorigenesis by inducing the production of inflammatory cytokines. We propose that upon liver injury, damage-associated molecular patterns released from dying hepatocytes activate liver macrophages to produce cytokines that promote tumor development. Strategies to block NOX1 or these cytokines might be developed to slow hepatocellular carcinoma progression.
The involvement of the homologous to E6-AP carboxyl terminus (HECT)-type E3s in crucial signaling pathways implicated in tumorigenesis is presently an area of intense research and extensive ...scientific interest. This review highlights recent discoveries on the ubiquitin-mediated degradation of crucial tumor suppressor molecules catalyzed by the HECT-type E3s. By providing a portrait of their protein targets, we intend to link the substrate specificity of HECT-type E3s with their contribution to tumorigenesis. Moreover, we discuss the relevance of targeting the HECT E3s, through the development of small-molecule inhibitors, as an anticancer therapeutic strategy.
Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic ...medications. Given evidence of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation and exerts its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1β production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. Metformin blocked LPS-induced ATP-dependent synthesis of the NLRP3 ligand mtDNA independently of AMP-activated protein kinase (AMPK) or NF-κB. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.
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•Metformin inhibits macrophage IL-1β and IL-6 production and blunts ARDS severity•Metformin inhibits cytosolic Ox-mtDNA production and NLRP3 inflammasome activation•By targeting ETCCI, metformin blocks macrophage ATP-dependent mtDNA synthesis•Myeloid targeted inhibition of mtDNA synthesis blunts IL-1β production and ARDS
The exact mechanism by which metformin exerts its anti-inflammatory effects is still not known. Xian et al. shows that metformin’s inhibition of ETCCI blocks ATP-dependent mtDNA synthesis, cytoplasmic ox-mtDNA generation and NLRP3 inflammasome activation in macrophages, independent of AMPK and NF-κB. By limiting IL-1β production, metformin blunts pulmonary inflammation.
The role of adaptive immunity in early cancer development is controversial. Here we show that chronic inflammation and fibrosis in humans and mice with non-alcoholic fatty liver disease is ...accompanied by accumulation of liver-resident immunoglobulin-A-producing (IgA
) cells. These cells also express programmed death ligand 1 (PD-L1) and interleukin-10, and directly suppress liver cytotoxic CD8
T lymphocytes, which prevent emergence of hepatocellular carcinoma and express a limited repertoire of T-cell receptors against tumour-associated antigens. Whereas CD8
T-cell ablation accelerates hepatocellular carcinoma, genetic or pharmacological interference with IgA
cell generation attenuates liver carcinogenesis and induces cytotoxic T-lymphocyte-mediated regression of established hepatocellular carcinoma. These findings establish the importance of inflammation-induced suppression of cytotoxic CD8
T-lymphocyte activation as a tumour-promoting mechanism.
Hepatocytes have important roles in liver iron homeostasis, abnormalities in which are tightly associated with liver steatosis and fibrosis. Here, we show that non-alcoholic fatty liver disease ...(NAFLD) and steatohepatitis (NASH) are characterized by iron-deficient hepatocytes and iron overload in hepatic stellate cells (HSCs). Iron deficiency enhances hepatocyte lipogenesis and insulin resistance through HIF2α-ATF4 signaling. Elevated secretion of iron-containing hepatocyte extracellular vesicles (EVs), which are normally cleared by Kupffer cells, accounts for hepatocyte iron deficiency and HSC iron overload in NAFLD/NASH livers. Iron accumulation results in overproduction of reactive oxygen species that promote HSC fibrogenic activation. Conversely, blocking hepatocyte EV secretion or depleting EV iron cargo restores liver iron homeostasis, concomitant with mitigation of NAFLD/NASH-associated liver steatosis and fibrosis. Taken together, these studies show that iron distribution disorders contribute to the development of liver metabolic diseases.
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•NAFLD/NASH livers present iron-deficient hepatocytes and iron overloaded HSCs•Hepatocyte iron deficiency enhances lipogenesis and insulin resistance via HIF2α-ATF4•Hepatocyte EVs shuttle iron into HSCs in NAFLD/NASH•Iron overload stimulates HSC ROS production and fibrogenic activation
Hepatocytes have important roles in liver iron homeostasis. Gao et al. report that hepatocyte-derived, iron-containing extracellular vesicles lead to hepatocyte iron deficiency and hepatic stellate cell iron overload, which contributes to the development of liver steatosis and fibrosis in Western diet-fed mice.
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