Table 2.
No. | Pathological Diseases | Disease Models | Involvement of Necroptosis | References | |
---|---|---|---|---|---|
1 | Neurological disease | Multiple sclerosis | Postmortem brain tissue samples of human patients; RIPK3−/− and Cuprizone-induced MS mice model | Increased RIPK1/-3 expression in microglia and macrophages in both human and mouse brain samples,Reduced cleaved caspase-8 expression | [69,70] |
EAE mice model | NF-κβ signaling mediated inflammatory response promotes FLIPL expression leading to necroptosis without caspase-8 activation | [70,71,72] | |||
Elevated expression of RIPK1, increased RIPK3 and MLKL phosphorylation in both microglia and oligodendrocytes primarily localized in the white matter of brain. | [70,73] | ||||
Amyotrophic sclerosis | SOD1G93A-mutated mice | Increased levels of RIPK1 and RIPK3 in MNs and astrocytes primarily localized in the spinal cord | [74,75,76] | ||
Optn−/− mice | Elevated levels of RIPK1, RIPK3 and pMLKL and necroptosis in the MNs of spinal cord | [76] | |||
TBK1−/− mice; TBK1−/− cell line | Higher level of RIPK1 and TNF-α induced necroptosis | [77,78] | |||
Alzheimer’s disease | Postmortem brain tissue samples and 23 AD, 24 p-preAD brain tissue samples from human patients; 5xFAD mice model | Elevated level of RIPK1/-3/MLKL at both mRNA and protein level | [79,80,81] | ||
Tg2576 APP/PS1 mice model | Higher RIPK1 activation drives Cst7 expression in microglia leads to lysosomal dysfunction and blocked proteostasis of deposit Aβ-plaques in AD | [80,82] | |||
cpdm mice model | Attenuation of M1 ubiquitination of RIPK1 to stimulate its activation | [83] | |||
Parkinson’s disease | OPA1-mutant PD patients derived iPSC; OPA1-A495V and OPA1-G488R neuronal cell lines | Higher phosphorylation level of RIPK1/-3/MLKL and mitochondrial dysfunction-induced necroptosis | [84] | ||
PD models (PC12 & SH-SY5Y cell line; 6-OHDA & MPTP mice model) | Promotes necrosome complex formation (RIPK1/-3/MLKL),ROS stimulated RIPK1 activation following with ASK1/JNK signaling activation | [84,85,86] | |||
2 | Renal disease | I/R-induced AKI | IRI C57BL/6 mouse model | RIPK3- and CypD and PPIF mediated mPT-dependent necroptosis | [87,88,89] |
Toxicant-induced AKI | FA-AKI renal mouse model | RIPK3/MLKL- and TWEAK-Fn14 axis-induced necroinflammation mediated necroptosis | [90,91] | ||
Cisplatin & Oxalate crystals nephrotoxicant mice model | RIPK3- and CypD-induced necroinflammation mediated necroptosis in the renal proximal tubular epithelial cells and whole kidney lysates,MLKL dependent necroptosis via higher MLKL membrane association in oxalate crystal-treated renal PTC cells | [92,93,94,95] | |||
Sepsis-induced AKI | CLP C57BL/6N mice model | RIPK3 induced higher OS and mitochondrial dysfunction via upregulation of NOX4 and mitochondrial complex-I/III inhibition | [96] | ||
Renal fibrosis CKD | RIPK3−/− UUO and AD fibrosis mice model | RIPK3 exacerbates kidney fibrogenesis via the PI3K-AKT dependent activation of ACL metabolic activity | [95] | ||
IRI mice model; OGBD treated PTC cell line | RIPK3/MLKL-dependent necroptosis mediated necroinflammation promotes renal interstitial fibrogenesis | [97] | |||
3 | Hepatic disease | Alcoholic liver disease | Chronic alcoholic mice model | CYP2E1-mediated higher RIP3 expression induces hepatocyte necroptosis during chronic alcohol treatment | [98] |
Gao-binge (chronic alcoholic) mice model | Impaired hepatic proteasome function via chronic alcohol exposure led to the higher accumulation of RIPK3 and induced necroptosis | [99,100] | |||
NAFLD and NASH diseases | HFCD and MCD diet mice model | TNF-α mediated RIPK3-dependent necroptosis, -oxidative stress and -necroinflammation in mice liver lysates | [101,102,103,104] | ||
FFC diet mice model | MLKL-dependent necroptotic signaling promotes FFC diet-induced liver injuries and necroinflammation via autophagy-flux inhibition | [105] | |||
4 | Pulmonary disease | Acute lung injuries (ALI) | VILI- induced ALI mice model | Impaired mitochondria-FAO metabolism pathway via MV exposure led to the RIPK3-dependent necroptosis mediates ALI pathogenesis | [106] |
LPS/ATP-induced ALI mice model | RIPK3 mediated NLRP3 inflammasome activation promotes lung injury via markedly increase inflammatory cell influx,IL-1α/β, IL-6, IL-18 secretion and HMGB1 release in infiltrating macrophages/monocytes cells | 133 | |||
Acute respiratory distress syndrome | Oleic acid-fed SD rat ARDS model | Elevated expression of TNF-α and RIPK1, RIPK3, MLKL in the BALF and lung tissue of OA-fed SD rat | [107] | ||
LPS-induced ARDS mice model | RIPK3-dependent necroptosis enhanced necroinflammation, ROS overgeneration and lung tissue injuries via increasing neutrophil infiltration and cytokines secretion in lung parenchyma tissue | [108,109] | |||
Sepsis/systemic inflammatory associated disorder (SIRS) | TNF-α induced SIRS mice model | RIPK1/-3 induced necroptosis with the DAMPs release and pro-inflammatory cytokines secretion associated with higher systemic inflammation and polymicrobial sepsis | [109] | ||
Cecal slurry-induced neonatal sepsis C57BL/6 mouse model | Elevated expression of RIPK1 and RIPK3 associated with systemic and pulmonary inflammation and lung injuries in neonatal sepsis | [110,111] | |||
Chronic obstructive pulmonary disease | Cigarette smoke (CS)-exposed Beas-2B cells and - C57BL/6 mice model | CS-induced mitoROS, mitochondrial dysfunction and mitophagy leads to necroptotic signaling activation with necroinflammation in pulmonary epithelial cells and alveolar macrophages | [112,113,114,115,116] | ||
Idiopathic pulmonary fibrosis (IPF) | BLM-induced IPF mice model | RIPK3 mediated necroptosis and DAMPs release induced necroinflammation and lung injury via increasing neutrophil infiltration and cytokines secretion in the alveolar epithelial cells | [117] | ||
5 | Cardiovascular disease | Heart failure | I/R or cardiotoxicant (doxorubicin) induced cardiac injury murine and pig model | Elevated level of RIPK1, RIPK3 and MLKL (phosphorylation) in the rat myocardial tissues, Detection of RIPK1/RIPK3 necrosome complex formation,Higher RIPK3 level caused activation of CAMKII as a results MPT opening and myocardial necroptosis | [118,119,120,121,122] |
Atherosclerosis | OxLDL- or APOE-deficient mice model | Higher RIPK3 activation and subsequent necroptosis induction atheroma macrophages leads to the local and systemic inflammation and atherosclerotic lesions | [123,124] | ||
Aortic aneurysm |
Elastase-induced AAA C57BL/6 mice model | Increased RIPK1 and RIPK3 level in aneurysmal tissues promotes AAA progression via caused SMC necroptosis and vascular inflammation (lymphocytes infiltration and DAMPs release) | [125,126] | ||
Calcium phosphate-induced AAA C57BL/6 mice model | GSK'074 treatment diminished AAA progression by impeding SMC necroptosis, necroinflammation (macrophages infiltration and cytokines secretion) and aortic expansion in aneurysm-prone aortae | [127] | |||
6 | Autoimmune diseases | Psoriasis | Primary epidermal keratinocytes cultured cells; Aldara-/IMQ- induced psoriasis mice models | Enhanced RIPK3 expression facilitates psoriatic inflammation by neutrophil-mediated cytokines/chemokines secretion,Elevated RIPK1/-3/MLKL expression, detection of their localization in all layers of epidermal skin cells confirmed by confocal microscopy. | [128,129,130] |
Rheumatoid arthritis (RA) | Collagen-induced arthritis mice model | Enhanced RIPK1/RIPK3/MLKL expression promotes NLRP3 inflammasome complex formation and cytokines secretion in the synovium joint tissue,IFN-γ diminished necroptosis-mediated RA progression by downregulation of MLKL expression | [131,132] | ||
7 | Cancer disease | Acute myeloid leukemia (AML) | DA1-3b p210BCR-ABL leukemia murine cell line; DA1-3b/C3HeOuJ mouse model | Reduced RIPK3 expression observed in clinical samples from human AML patients was independently associated with poor prognosis,RIPK3 downregulation suggest diminished necroptosis via p65/RelA cleavage and as results shift towards NF-κβ mediate cell survival in DA1-3b leukemia cells | [133] |
Chronic lymphocytic leukemia (CLL) | Primary CLL cells from human CLL patients | Lower expression of RIPK3 and CYLD reduced TNF-α/zVAD mediated necroptosis in CML cells | [134] | ||
Head and neck squamous cell carcinoma (HNSCC) | Primary and metastatic cell lines and tissues from human HNSCC patients | Enhanced genomic methylation of RIPK1 promoter caused reduced TLR3-mediated apoptosis/necroptosis with higher tumor cells migration in HNSCC metastatic cells,Loss of RIPK1 expression strongly linked with metastatic disease in a cohort of HNSCC patients | [135] | ||
Non-small cell lung cancer (NSCLC) | Clinical samples from 253 and 394 NSCLC human patients | Lower RIPK1/-3/MLKL expression was linked with poor prognosis in a NSCLC tissues associated with reduced levels of necroptosis signaling, Lower RIPK1 and PELI with higher p53 expression found to be linked with a worse OS of stage-I NSCLC patients |
[136] | ||
Ovarian cancer | Clinical samples from 75 human ovarian cancer patients | Low MLKL level was significantly linked with both reduced DFS and OS of patients with ovarian cancer, MLKL serves as a potential prognosis marker in ovarian cancer patients | [137] | ||
Colon cancer | HT29, Colo205, HCT116, SW480 colon cancer cell lines; Colon cancer tissues samples from human colon cancer patients | Reduce RIPK1 and RIPK3 expressions (due to hypoxia) resists cancer cells to chemotherapeutic agents-induced necroptotic cell death; Poly I:C induces TLR3/RIP3-dependent necroptosis and tumor growth inhibition via induction of DC cells mediated anti-tumor activity in colon cancer tissues |
[138] | ||
Cervical cancer | HPV18-positive HeLa and C4-I cervical carcinoma cell lines | RIPK3-upregulation stimulates IL1-α secretion from Poly I:C-induced necroptotic cervical cancer cells leads to activation DC cells, selective activation of DC cells shows anti-tumor effects via producing cytotoxic cytokine IL-12 or activating CD8+ T-cells | [139] | ||
Melanoma | DM733, DM598, DM738 and DM833 melanoma cell lines; A2058 cells injected NCr-nu/nu miceB16 mouse melanoma cell lines and B16 cells injected C57Bl/6 mice melanoma metastasis model | Selective inhibition of CYLD expression and activation of JNK/AP-1 and β1-integrin signaling by Snail is critical to protects melanoma from necroptosis in melanocytes and nevus cells, zVAD-fmk in combination with RT, CT, HT increased necroptosis in B16-F10 melanoma cells concomitantly with HMGB1 secretion and increase cytotoxic DCs as well as CD8+ T-cells infiltration around tumor microenvironment. RIPK3 upregulation induces NK T-cells mediated anti-tumor responses via mitochondrial PGAMF-NFAT/Drp1 signaling activation in metastatic melanoma tumor cells;Increased RIPK1 expression positively linked with the higher metastatic rate and a poor prognosis in melanoma potentially due to NF-κβ-mediated pro-tumorigenic abilities |
[140,141,142] | ||
Glioblastoma | Tissue samples from human glioblastoma patients | Increased RIPK1 levels prevents p53 induction via augmenting mdm2 level and NF-κβ signaling activation to confers a poor prognosis in glioblastoma | [143] | ||
Lung cancer | HBEC-2, HBEC-13 and BEAS-2B cell lines; Cigarette smoke/Benzo(a)pyrene-exposed mouse lung tumor model | Higher RIPK1 expression promotes BPDE-induced malignant transformation of HBEC cells by catalase-mediated suppression of ROS overproduction as well as MAPKs signaling deactivation | [144] | ||
Breast cancer | Clinical samples of human breast cancer patients; MDA-MB231, 4T1, MCF10A and MCF12A breast cancer cell lines; MDA-MB-231/4T1 xenografted Balb/C mice model | Nearly 85% patients of breast cancer have reduced RIPK3 expression that was associated with a worse prognosis, Lower RIPK3 expression suggest by genomic methylation of transcription factor in its transcriptional sites in breast cancer cells; Lower RIPK1/-3/MLKL expression found to be linked with reduced breast cancer tumorigenicity due to impairment of NF-κβ-mediated pro-tumor growth cytokines secretion |
[142] | ||
Pancreatic adenocarcinoma (PAC) | Tissue samples from 80 human PAC patients; AsPC1, PANC1, and MIA PaCa-2 pancreatic cancer cell lines; KrasG12D PDEC/ FC1242 cells xenografted C57BL/6 mice | Decreased MLKL expression was strongly correlated with cancer progression with diminished necroptosis, MLKL serves as a therapeutic targets in PAC cells, RIPK1/-3 dependent necroptosis signaling promotes pancreatic tumorigenicity through enhancing CXCL1 and Mincle-induced adaptive immune suppression in tumor-infiltrating myeloid cells; Higher RIPK3 and MLKL levels promotes the pancreatic cancer cells migration and invasion via the activation of CXCL5-CXCR2 axis |
[145] |