TABLE 1.
The role of necroptosis in pulmonary diseases.
| Disease | More specific | Main content about necroptosis | References |
|---|---|---|---|
| In infection | S. aureus pneumonia | The accessory gene regulator (agr) quorum sensing system can be inhibited by the heptapeptide RNAIII-inhibiting peptide, which dampens (Phenol-soluble modulins) PSMα-induced neutrophil necroptosis | Zhou et al. (2018) |
| S. aureus activates the NLRC4 to suppress γδ T cell-derived IL-17A-dependent neutrophil recruitment by driving necroptosis and IL-18 production, which impedes host defense | Paudel et al. (2019) | ||
| NLRP6 expression is increased, triggering necroptosis and hyper-inflammation via the TNF-α pathway, leading to the loss of neutrophils by dampening IFN-γ and ROS production | Ghimire et al. (2018) | ||
| Agr-regulated toxins activate necroptosis and IL-1β expression, leading to alveolar macrophage depletion and lung injury | Kitur et al. (2015) | ||
| Bacterial PFTs | PFTs-induced respiratory epithelial cell RIP1/RIP3/MLKL-dependent necroptosis, as a result of influenza-induced oxidative stress, was triggered by ion dysregulation through PFT-mediated membrane permeabilization | Gonzalez-Juarbe et al. (2017), Gonzalez-Juarbe et al. (2020) | |
| PFTs induce necroptosis of macrophages through ion dysregulation, mitochondrial damage, ATP depletion, and oxidative stress | Gonzalez-Juarbe et al. (2015) | ||
| PETs-induced necroptosis plays a beneficial role in facilitating adaptive immune response through the release of inflammatory factors | Riegler et al. (2019) | ||
| Klebsiella pneumoniae (KPn) | KPn infection damage the neutrophil efferocytosis by inducing necroptosis of neutrophils | Jondle et al. (2018) | |
| Mycobacterium tuberculosis (Mtb) | TNFα excess triggers ROS production then induces RIPK1-RIPK3-dependent necroptosis of macrophages, leading to bacterial dissemination | Roca and Ramakrishnan (2013) | |
| TNFα excess leads to RIPK1-RIPK3-dependent necroptosis in murine fibroblasts and RIPK1-dependent necrosis-like cell death in murine macrophages | Butler et al. (2017) | ||
| Virulent Mtb evasion of macrophages apoptosis and immunity by Bcl-xL, inducing RIPK3–impendent necrosis and preventing caspase 8-activation | Zhao et al. (2017) | ||
| The inhibition of necroptosis by MLKL-deficiency or Nec-1 in humanized mice does not affect Mtb infection progression | Stutz et al. (2018a) | ||
| RIPK3 is not an important mediator of pathological inflammation or macrophage necrosis in Mtb, for the reason is that inhibition of RIPK3 is not effective | Stutz et al. (2018b) | ||
| Influenza A virus | RIPK3 is activated by IAV and plays a crucial role in antiviral immunity by activating MLKL-dependent necroptosis with RIPK3 kinase activity and FADD-mediated apoptosis. ZBP1 is the link between IAV and RIPK3 activation, and ZBP1 deficiency is resistant to IAV-triggered necroptosis and apoptosis | Downey et al. (2017) | |
| RIPK3 is activated by IAV and plays a crucial role in antiviral immunity by activating MLKL-dependent necroptosis with RIPK3 kinase activity and FADD-mediated apoptosis. ZBP1 is the link between IAV and RIPK3 activation, and ZBP1 deficiency is resistant to IAV-triggered necroptosis and apoptosis | Nogusa et al. (2016), Thapa et al. (2016) | ||
| Z-RNAs generated by replicating IAV activate ZBP1, activating RIPK3 and MLKL, thus leading to nuclear membrane rupture and resulting in a nucleus-to-cytoplasm necroptosis. In unrestrained cell death, MLKL-induced nuclear rupture causes exceeding and deleterious inflammatory responses, which drive IAV disease severity | Zhang et al. (2020) | ||
| RSV | RSV induces RIPK3-MLKL-dependent necroptosis of macrophages by activating TLR4/TLR3 and pyroptosis through activating TLR2 and triggering ROS generation | Bedient et al. (2020) | |
| ALI/ARDS | Influenza A H7N9 virus | Low expression of cIAP2 caused RIPK1/3-dependent necroptosis of airway epithelial cells, leading to ALI/ARDS and death | Qin et al. (2019) |
| OA-induced ALI/ARDS | RIPK3/MLKL-independent necroptosis is obviously activated, while lung edema and inflammation is reduced by Nec-1 | Pan et al. (2016b) | |
| LPS-induced ALI/ARDS | Plasma RIPK3 is associated with ALI/ARDS. RIPK3 depletion reduced inflammatory mediators and ameliorated lung tissue injury | Wang et al. (2016), Shashaty et al. (2019) | |
| LPS induces ZBP-1 expression, which causes RIK3/MLKL-dependent necroptosis that results in the release of DAMPs to activate the TLR9/NF-κB pathway and macrophages release pro-inflammatory cytokines, leading to lung inflammation and injury | Du et al. (2019) | ||
| The expression of CXCR1/2 and p-MLKL is high, and the SP level is high while the VIP level is low. All could be reversed by reparixin, a CXCR antagonist that increased the survival rate mice of mice and improved lung inflammation | Wang et al. (2018b) | ||
| hyperoxic acute lung injury (HALI) | Hyperoxia exposure causes necroptosis with increased expression of RIPK1, RIPK3, and MLKL by oxidative stress, leading to inflammatory infiltration and pulmonary edema. Hyperoxia-induced miR-185-5p promotes both apoptosis and necroptosis | Han et al. (2018), Carnino et al. (2020) | |
| Hydrogen sulfide (H2S) | H2S exposure results in lung injury, immune suppression, inflammatory response, and necroptosis or other cell death. LncRNA3037/miR-15a/BCL2-A20 signaling could be involved in these | Li et al. (2020b), Liu et al. (2020b) | |
| Ventilator-induced lung injury (VILI) | Plasma RIPK3 levels are higher in patients with mechanical ventilation (MV) and RIPK3 deficiency confer protection against VILI. | Siempos et al. (2018) | |
| Red blood cell (RBC) transfusions | RBC transfusion triggers RIPK3-dependent necroptosis of lung endothelial cells with the release of HMGB1, leading to lung inflammation and damage. Advanced Glycation End Products (RAGE) could be an essential mediator | Qing et al. (2014), Faust et al. (2020) | |
| Lung transplantation | Prolonged cold-ischemia-induced ischemia-reperfusion causes RIPK3/MLKL-dependent necroptosis via calpain-STAT3-RIPK axis activation, leading to predisposing lung grafts to primary graft dysfunction (PGD) | Kim et al. (2018), Wang et al. (2019a) | |
| Renal allografts | Regulated necrosis including parthanatos and necroptosis involve in part of the mechanism of renal graft injury that leads to lung injury, and necroptosis mediated by OPN signaling in pancreatitis-associated lung injury | Zhao et al. (2015), Zhao et al. (2019a) | |
| SARS-CoV-2 | SARS-CoV-2 activates caspase-8, leading to caspase-8-mediated apoptosis and inflammatory response, and RIPK3-MLKL-dependent necroptosis without fully inhibited by caspase-8. The dual modes of cell death pathways play a dual role in appropriately immune responses to restrict viral replication or severe lung damage as a hyperactivation status | Li et al. (2020a) | |
| The combination of TNF-a and IFN-g induced the JAK/STAT1/IRF1 axis activation, leading necroptosis and other inflammatory cell death processes that could be one of the possible mechanisms linking cytokine storm to organ damage | Karki et al. (2021) | ||
| Asthma | RSV | RSV-induced necroptosis results in the release of HMGB1 and neutrophilic that contributes to RSV bronchiolitis pathogenesis inflammation. Inhibition of necroptosis attenuated the pathologies that will ameliorate asthma progression in later-life | Simpson et al. (2020) |
| MUC1 | TNF-α could induce necroptosis of 16HBE cells accompanied by the upregulation of MUC1, while MUC1 downregulation increase necroptosis and inhibit the effects of anti-necroptosis by Dex | Zhang et al. (2019a), Zhang et al. (2019b) | |
| Aspergillus-induced asthma model | RIPK3-MLKL necroptosis induce the release of bioactive IL-33, which can activate basophils and eosinophils, leading to exacerbating of allergic inflammation | Shlomovitz et al. (2019) | |
| Adhesion-induced eosinophil cytolysis | RIPK1-independent necroptosis take part in adhesion-induced eosinophil cytolysis, which is required p38 MAPK and NADPH oxidase activation | Radonjic-Hoesli et al. (2017) | |
| particulate matter (PM) | PM2. 5 results in airway Hyperresponsiveness and trachea injury by necroptosis, which induces neutrophils and IL-17 to inflammation | Zhao et al. (2019b) | |
| COPD | PM | Airborne PM exposure induces oxidative stress that can trigger necroptosis, leading to PM-induced pulmonary inflammation and mucus hyperproduction | Peixoto et al. (2017), Xu et al. (2018) |
| Cigarette Smoke (CS) | Induces necroptosis of lung structural cells with a release of DAMPs, leading to neutrophilic airway inflammation, which is suppressed with inhibition of GRP78 | Pouwels et al. (2016), Wang et al. (2018c), Wang et al. (2020c) | |
| Triggers mitophagy-dependent necroptosis via PINK1 stabilization with mitophagy, in which C16-Cer could be an upstream initiator, while highC24-DHC levels might protect against CS-induced necroptosis | Mizumura et al. (2014), Mizumura et al. (2018) | ||
| Idiopathic Pulmonary Fibrosis | BLM-induced model | The level of RIPK3 expression is increased in lung tissue from IPF patients. ROS production by BLM triggers RIPK3-dependent necroptosis, which takes part in fibrosis development through inflammatory cell accumulation via the release of DAMPs | Lee et al. (2018) |
| SFTPA1 | JNK-mediated the overexpress of RIPK3, which triggers necroptosis of AEII cells in Sftpa1-KI mice, leading to pulmonary fibrosis | Takezaki et al. (2019) | |
| Pulmonary arterial hypertension | PAH severity | Necroptosis and necrosis play a potential role in HMGB1 release, activation of TLR4, and the manifestation of sex difference in PAH severity | Zemskova et al. (2020) |
| Monocrotaline-induced PAH | RIPK3-mediated necroptosis is involved in the generation of DAMPs that was associated with the activation of TLR and NLR pathways by bioinformatics analysis | Xiao et al. (2020) | |
| Lung cancer | Metastasis | Induce necroptosis of endothelial cells leading to extravasation and metastasis via amyloid precursor protein and DR6, a primary mediator | Strilic et al. (2016) |
| TAK1 deficiency is more likely to cause RIPK3-dependent necroptosis of human/murine endothelial cells by Up-regulating the expression of RIPK3 and form metastases by endothelial | Yang et al. (2019) | ||
| Prognosis in NSCLC | The high level of RIPK3 was associated with improved local control(LC) and progression-free survival (PFS) after hypofractionated radiation therapy. But low RIPK3 showed worse disease free survival (DFS) after curative resection and worse chemotherapy response | Wang et al. (2018a), Park et al. (2020), Wang et al. (2020a) | |
| Higher RIPK3 expression is associated with a shorter OS and a tendency of shorter DFS, which reason might be the effect of resistance to radiotherapy or excessive necroptosis-mediated damage | Kim et al. (2020) |