Ripk1

ZBP1 is an interferon (IFN)-induced nucleic acid (NA) sensor that senses unusual Z-form NA (Z-NA) to promote cell death and inflammation. However, the mechanisms that dampen ZBP1 activation to fine-tune inflammatory responses are unclear. Here, we characterize a short isoform of ZBP1 (referred to as ZBP1-S) as an intrinsic suppressor of the inflammatory signaling mediated by full-length ZBP1. Mechanistically, ZBP1-S depresses ZBP1-mediated cell death by competitive binding with Z-NA for Zα domains of ZBP1...

Acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) is a severe complication of sepsis characterized by acute respiratory distress, hypoxemia, and diffuse bilateral pulmonary infiltrates. The regulation of RIPK1 is an important part of the inflammatory response, and cIAP1/2 serves as the E3 ubiquitin ligase for RIPK1. In this study, we investigated the effect and mechanism of cIAP1/2 inhibition on sepsis-induced lung injury. Our results showed that cIAP1/2 inhibition can alleviate sepsis-induced lung injury and reduce the inflammatory response, which is accompanied by downregulation of RIPK1 phosphorylation and ubiquitination...

BACKGROUND: Cardiomyocyte apoptosis plays a vital role in myocardial ischemia-reperfusion (MI/R) injury; however, the role of beclin1 (BECN1) remains unclear. This study aimed at revealing the function of BECN1 during cardiomyocyte apoptosis after MI/R injury. METHODS: In vivo, TTC and Evan's blue double staining was applied to verify the gross morphological alteration in both wild type (WT) mice and BECN1 transgene mice (BECN1-TG), and TUNEL staining and western blot were adopted to evaluate the cardiomyocyte apoptosis...

RIPK1 is a multi-functional kinase that regulates cell death and inflammation and has been implicated in the pathogenesis of inflammatory diseases. RIPK1 acts in a kinase-dependent and kinase-independent manner to promote or suppress apoptosis and necroptosis, but the underlying mechanisms remain poorly understood. Here, we show that a mutation (R588E) disrupting the RIPK1 death domain (DD) caused perinatal lethality induced by ZBP1-mediated necroptosis. Additionally, these mice developed postnatal inflammatory pathology, which was mediated by necroptosis-independent TNFR1, TRADD, and TRIF signaling, partially requiring RIPK3...

There is increasing need to expand availability of donor liver grafts, including steatotic livers. However, the current use of steatotic grafts in liver transplantation is less acceptable due to their higher susceptibility to ischemia-reperfusion (I/R) injury. To investigate the mechanism underlying the susceptibility of steatotic liver to I/R injury, we detected cell death markers and inflammation in clinical donor livers and animal models. We found that caspase-8-mediated hepatic apoptosis is activated in steatotic liver I/R...

Necroptosis has emerged as one of the crucial pathological processes involved in the regulation of cell death and inflammation in chronic obstructive pulmonary disease (COPD). Airway epithelial necroptosis is closely linked to COPD pathogenesis. Necroptotic lung cells can release damage-associated molecular patterns (DAMPs) that can initiate a robust inflammatory response. However, the underlying mechanism of necroptosis in COPD is still not clearly understood. Therefore, we aimed to explore the roles and mechanisms of receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-mediated necroptosis in the regulation of inflammatory responses in COPD to provide insights into RIPK1-inhibitor drug discovery efforts and their therapeutic benefits in COPD...

Hepatitis delta virus (HDV) infection represents the most severe form of human viral hepatitis; however, the mechanisms underlying its pathology remain incompletely understood. We recently developed an HDV mouse model by injecting adeno-associated viral vectors (AAV) containing replication-competent HBV and HDV genomes. This model replicates many features of human infection, including liver injury. Notably, the extent of liver damage can be diminished with anti-TNF-α treatment. Here, we found that TNF-α is mainly produced by macrophages...

The T cell population size is stringently controlled before, during, and after immune responses, as improper cell death regulation can result in autoimmunity and immunodeficiency. RIPK1 is an important regulator of peripheral T cell survival and homeostasis. However, whether different peripheral T cell subsets show a differential requirement for RIPK1 and which programmed cell death pathway they engage in vivo remains unclear. In this study, we demonstrate that conditional ablation of Ripk1 in conventional T cells (Ripk1ΔCD4 ) causes peripheral T cell lymphopenia, as witnessed by a profound loss of naive CD4+ , naive CD8+ , and FoxP3+ regulatory T cells...

Mucosal epithelial death is an essential pathological characteristic of portal hypertensive gastropathy (PHG). FADDosome can regulate mucosal homeostasis by controlling mitochondrial status and cell death. However, it remains ill-defined whether and how the FADDosome is involved in the epithelial death of PHG. The FADDosome formation, mitochondrial dysfunction, glycolysis process and NLRP3 inflammasome activation in PHG from both human sections and mouse models were investigated. NLRP3 wild-type ( NLRP3 -WT) and NLRP3 knockout ( NLRP3 -KO) littermate models, critical element inhibitors and cell experiments were utilized...

BACKGROUND: Fibrosis results from excessive scar formation after tissue injury. Injured cells release alarmins such as interleukin 1 (IL-1) α and β as primary mediators initiating tissue repair. However, how alarmins from different cell types differentially regulate fibrosis remains to be explored. METHODS: Here, we used tissue specific knockout strategy to illustrate a unique contribution of endothelial cell-derived IL-1α to lung and liver fibrosis...

The dynamic interface between invading viral pathogens and programmed cell death (PCD) of the host is a finely regulated process. Host cellular demise at the end of the viral life cycle ensures the release of progeny virions to initiate new infection cycles. Rotavirus (RV), a diarrheagenic virus with double-stranded RNA genome, has been reported to trigger different types of PCD such as apoptosis and pyroptosis in a highly regulated way to successfully disseminate progeny virions. Recently our lab also showed that induction of MLKL-driven programmed necroptosis by RV...

Fas-associated protein with death domain (FADD), procaspase-8, and cellular FLICE-inhibitory proteins (cFLIP) assemble through death-effector domains (DEDs), directing death receptor signaling towards cell survival or apoptosis. Understanding their three-dimensional regulatory mechanism has been limited by the absence of atomic coordinates for their ternary DED complex. By employing X-ray crystallography and cryogenic electron microscopy (cryo-EM), we present the atomic coordinates of human FADD-procaspase-8-cFLIP complexes, revealing structural insights into these critical interactions...

Fumonisin B1 (FB1), one of the most widely distributed mycotoxins found in grains and feeds as contaminants, affects many organs including the kidney once ingested. However, the nephrotoxicity of FB1 remains to be further uncovered. The connection between necroptosis and nephrotoxicity of FB1 has been investigated in this study. The results showed that mice exposed to high doses of FB1 (2.25 mg/kg b.w.) developed kidney damage, with significant increases in proinflammatory cytokines (Il-6, Il-1β), kidney injury-related markers (Ngal, Ntn-1), and gene expressions linked to necroptosis (Ripk1, Ripk3, Mlkl)...

Tanshinone IIA (Tan IIA), a main active ingredient of salvia miltiorrhiza, has a wide range of antitumor effects, while its specific role and mechanism in head and neck squamous cell carcinomas (HNSCC) is not fully understood. Totally 59 primary HNSCC patients underwent two courses of induction chemotherapy before surgery. The association between expression of Fas-Associated Death Domain (FADD) and receptor interacting protein kinase 1 (RIPK1) and chemotherapy resistance and survival were evaluated. The cell counting kit-8 was used to detect the effect of Tan IIA on the activity of cisplatin in chemoresistant HNSCC cells through a series of in vitro experiments...

BACKGROUND: Inflammation and subsequent mitochondrial dysfunction and cell death worsen outcomes after revascularization in ischemic stroke. Receptor-interacting protein kinase 1 (RIPK1) activated dynamin-related protein 1 (DRP1) in a NLRPyrin domain containing 3 (NLRP3) inflammasome-dependent fashion and Hypoxia-Inducible Factor (HIF)-1α play key roles in the process. This study determined how phenothiazine drugs (chlorpromazine and promethazine (C + P)) with the hypothermic and normothermic modality impacts the RIPK1/RIPK3-DRP1 and HIF-1α pathways in providing neuroprotection...

OBJECTIVE: The specific mechanisms of sevoflurane-induced neurotoxicity are still undetermined. The aim of the current study was to investigate the role of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway in sevoflurane-induced neuronal necroptosis. METHODS: BV2 microglial cells were divided into a control group and a 4% sevoflurane exposure group. Western blotting was used to detect expression of the M1 polarization marker inducible nitric oxide synthase (iNOS)...

Receptor-interacting protein kinase 3 (RIPK3), a member of the receptor-interacting protein kinase (RIPK) family with serine/threonine protein kinase activity, interacts with RIPK1 to generate necrosomes, which trigger caspase-independent programmed necrosis. As a vital component of necrosomes, RIPK3 plays an indispensable role in necroptosis, which is crucial for human life and health. In addition, RIPK3 participates in the pathological process of several infections, aseptic inflammatory diseases, and tumors (including tumor-promoting and -suppressive activities) by regulating autophagy, cell proliferation, and the metabolism and production of chemokines/cytokines...

BACKGROUND: Necroptosis has emerged as a novel molecular pathway that can be targeted by chemotherapy agents in the treatment of cancer. OSW-1, which is derived from the bulbs of Ornithogalum saundersiae Baker, exerts a wide range of pharmacological effects. AIM: To explore whether OSW-1 can induce necroptosis in colorectal cancer (CRC) cells, thereby expanding its range of clinical applications. METHODS: We performed a sequence of functional experiments, including Cell Counting Kit-8 assays and flow cytometry analysis, to assess the inhibitory effect of OSW-1 on CRC cells...

ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium nobile Lindl. (DNL) is a well-known traditional Chinese medicine that has been recorded in the Chinese Pharmacopoeia (2020 edition). The previous data showed that Dendrobium nobile Lindl. alkaloids (DNLA) protect against CCl4 -induced liver damage via oxidative stress reduction and mitochondrial function improvement, yet the exact regulatory signaling pathways remain undefined. AIM OF THE STUDY: The aim of the present study was to investigate the role of necroptosis in the mode of CCl4 -induced liver injury and determine whether DNLA protects against CCl4 -induced acute liver injury (ALI) by inhibiting mitochondrial ROS (mROS)-mediated necroptosis...

The monogenic causes of very-early-onset inflammatory bowel disease (VEO-IBD) have been defined by genetic studies, which were usually related to primary immunodeficiencies. Receptor-interacting serine/threonine-protein kinase-1 (RIPK1) protein is an important signalling molecule in inflammation and cell death pathways. Its deficiency may lead to various clinical features linked to immunodeficiency and/or inflammation, including IBD. Here, we discuss an infant with malnutrition, VEO-IBD, recurrent infections and polyathritis who has a homozygous partial deletion in RIPK1 gene...