c-Jun N-terminal kinases differentially regulate TNF- and TLRs-mediated necroptosis through their kinase-dependent and -independent activities

Cao, Meiqun; Chen, Fei; Xie, Ni; Cao, Mengyao; Chen, Pengfei; Lou, Qi; Zhao, Yanli; He, Chen; Zhang, Shuyuan; Song, Xiaohe; Sun, Yu; Zhu, Weimin; Mou, Lisha; Luan, Shaodong; Gao, Hanchao

doi:10.1038/s41419-018-1189-2

Cited by 54 publications

(39 citation statements)

References 48 publications

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“…In vitro studies show activation of mammalian Toll-like receptors (TLRs) can trigger necroptotic cell death through RIPK1, RIPK3, and pseudokinase mixed lineage kinase-domainlike (MLKL) complex [45,46]. Intriguingly, inhibition of JNK with SP600125 restricts TLRs-induced necroptosis in macrophages, whereas loss of JNK by short-interfering RNA (siRNA) augments TLRs-induced necroptotic cell death, suggesting a dual role for JNK in regulating necroptosis [47]. Recent studies in Drosophila suggest that Toll signaling, consisting of the Toll ligand Spätzle, several Toll-related receptors and NF-kB factors, is required for apoptotic cell death of loser cell elimination during epithelial cell competition, which up-regulates the expression of pro-apoptotic genes, yet this function of Toll signaling is independent of the JNK activity [48][49][50][51].…”

Section: Discussionmentioning

confidence: 99%

Toll signaling promotes JNK-dependent apoptosis in Drosophila

Xiang

et al. 2020

Cell Div

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Background: Apoptosis plays pivotal roles in organ development and tissue homeostasis, with its major function to remove unhealthy cells that may compromise the fitness of the organism. Toll signaling, with the ancient evolutionary origin, regulates embryonic dorsal-ventral patterning, axon targeting and degeneration, and innate immunity. Using Drosophila as a genetic model, we characterized the role of Toll signaling in apoptotic cell death. Results: We found that gain of Toll signaling is able to trigger caspase-dependent cell death in development. In addition, JNK activity is required for Toll-induced cell death. Furthermore, ectopic Toll expression induces the activation of JNK pathway. Moreover, physiological activation of Toll signaling is sufficient to produce JNK-dependent cell death. Finally, Toll signaling activates JNK-mediated cell death through promoting ROS production. Conclusions: As Toll pathway has been evolutionarily conserved from Drosophila to human, this study may shed light on the mechanism of mammalian Toll-like receptors (TLRs) signaling in apoptotic cell death.

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Section: Discussionmentioning

confidence: 99%

Toll signaling promotes JNK-dependent apoptosis in Drosophila

Xiang

et al. 2020

Cell Div

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“…Triggering of Msr1 has recently been shown to induce JNK signaling pathway activation (8). JNK signaling is a stress-activated pathway that has been implemented in saturated fatty acid (SFA)-induced pro-inflammatory activation of macrophages (7,17). Indeed, HFD-fed Msr1 -/mice exhibited reduced hepatic JNK1/2 phosphorylation compared to the WT (Fig.…”

Section: Fig 1 Macrophage Scavenger Receptor 1 (Msr1) Expression Inmentioning

confidence: 97%

Macrophage Scavenger Receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease

Govaere

Martínez–López

Petersen

et al. 2020

Preprint

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Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), however the exact mechanisms remain incompletely understood. Here we demonstrate that macrophage scavenger receptor 1 (MSR1) is associated with the occurrence of hepatic lipid-laden foamy macrophages and correlates with the degree of steatosis and steatohepatitis in a large cohort of NAFLD patients. Mice lacking Msr1 are protected against high fat diet-induced metabolic disorder, showing less hepatic inflammation and fibrosis, reduced circulating fatty acids, increased lipid storage in the adipocytes and improved glucose tolerance. Moreover, MSR1 triggers diet-induced JNK-mediated inflammatory activation of macrophages independent of lipopolysaccharide. Taken together, our data suggest a critical role for MSR1 in lipid homeostasis and a potential therapeutic target for the treatment of NAFLD.One Sentence SummaryThe immunometabolic role of MSR1 in human NAFLD.

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“…We 14,15 and others [37][38][39] have shown previously that TLR4 signaling on the intestinal epithelium plays a critical role in NEC development through the development of an inflammatory response and breakdown of the intestinal barrier. Of note, necroptosis in a variety of cells may be induced by TLR4 signaling, [40][41][42] suggesting perhaps that TLR4 activation could be upstream of necroptosis in the pathogenesis of NEC. In support of this possibility, injection of wild-type mice with the TLR4 ligand lipopolysaccharide (LPS) caused upregulation of the inflammatory cytokine interleukin 6 (IL6) in the intestine, as measured by qRT-PCR, as well as by upregulation of necroptosis gene expression, linking TLR4 activation with necroptosis in the neonatal mouse intestine ( Figure 5A).…”

Section: Necroptosis Is Activated Downstream Of Tlr4 Signaling In Thementioning

confidence: 99%

A Novel Role for Necroptosis in the Pathogenesis of Necrotizing Enterocolitis

Werts

Fulton

Ladd

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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Necrotizing enterocolitis is a devastating disease of prematurity characterized by gram-negative bacteria colonization and enterocyte death. We identify a role of Toll-like receptor 4-mediated necroptosis of the intestinal epithelium as a precursor to necrotizing enterocolitis development. BACKGROUND & AIMS: Necrotizing enterocolitis (NEC) is a devastating disease of premature infants characterized by Toll-like receptor 4 (TLR4)-dependent intestinal inflammation and enterocyte death. Given that necroptosis is a proinflammatory cell death process that is linked to bacterial signaling, we investigated its potential role in NEC, and the mechanisms involved. METHODS: Human and mouse NEC intestine were analyzed for necroptosis gene expression (ie, RIPK1, RIPK3, and MLKL), and protein activation (phosphorylated RIPK3). To evaluate a potential role for necroptosis in NEC, the effects of genetic (ie, Ripk3 knockout or Mlkl knockout) or pharmacologic (ie, Nec1s) inhibition of intestinal inflammation were assessed in a mouse NEC model, and a possible upstream role of TLR4 was assessed in Tlr4-deficient mice. The NEC-protective effects of human breast milk and its constituent milk oligosaccharides on necroptosis were assessed in a NEC-in-a-dish model, in which mouse intestinal organoids were cultured as either undifferentiated or differentiated epithelium in the presence of NEC bacteria and hypoxia. RESULTS: Necroptosis was activated in the intestines of human and mouse NEC in a TLR4-dependent manner, and was upregulated specifically in differentiated epithelium of the immature ileum. Inhibition of necroptosis genetically and pharmacologically reduced intestinal-epithelial cell death and mucosal inflammation in experimental NEC, and ex vivo in the NEC-in-a-dish system. Strikingly, the addition of human breast milk, or the human milk oligosaccharide 2 fucosyllactose in the ex vivo system, reduced necroptosis and inflammation. CONCLUSIONS: Necroptosis is activated in the intestinal epithelium upon TLR4 signaling and is required for NEC development, and explains in part the protective effects of breast milk.

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c-Jun N-terminal kinases differentially regulate TNF- and TLRs-mediated necroptosis through their kinase-dependent and -independent activities

Cited by 54 publications

References 48 publications

Toll signaling promotes JNK-dependent apoptosis in Drosophila

Toll signaling promotes JNK-dependent apoptosis in Drosophila

Macrophage Scavenger Receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease

A Novel Role for Necroptosis in the Pathogenesis of Necrotizing Enterocolitis

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