Skip to main content
NCBI home page
Journal of Central South University Medical Sciences logoLink to Journal of Central South University Medical Sciences
. 2022 Sep 28;47(9):1289–1298. doi: 10.11817/j.issn.1672-7347.2022.210501

Necroptosis in inflammatory bowel disease: A potential effective target

炎症性肠病中的坏死性凋亡：一个潜在的治疗靶点（英文）

LONG Xiuyan 1,1, ZHU Ningxin 1, QIU Jianing 2, YU Xiaoyu 1, RUAN Xixian 1, WANG Xiaoyan 1,✉, TIAN Li 1,✉
Editor: PENG Minning
PMCID: PMC10930328  PMID: 36411714

Abstract

The morbidity of inflammatory bowel diseases (IBD) is rising rapidly but no curative therapies to prevent its recurrence. Cell death is crucial to maintaining homeostasis. Necroptosis is a newly identified programmed cell death and its roles played in IBD need to be explored. Necroptosis is mediated by receptor interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL), which resulted in cell swelling, plasma membrane rupture, intracellular content leaking, and eventually cell death as well as the promotion of inflammation. Studies have found that inhibiting necroptosis alleviated IBD in animal models and IBD patients with an increased level of necroptosis in inflammatory tissues, indicating that necroptosis is related to the pathogenesis of IBD. However, due to the complexity in regulation of necroptosis and the involvement of multiple functions of relevant signaling molecules, the specific mechanism remains elusive. Necroptosis may play a vital regulatory role in the pathogenesis of IBD, which provides a new idea and method for further exploring the therapeutic target of IBD.

Keywords: inflammatory bowel disease, necroptosis, receptor interacting protein kinase 1, receptor interacting protein kinase 3, mixed lineage kinase domain-like protein

Inflammatory bowel disease (IBD) is a group of chronic nonspecific intestinal inflammatory diseases with unclear etiology, including ulcerative colitis (UC) and Crohn’s disease (CD). IBD is prone to relapse and cannot be cured. Hence, IBD is called “a green tumor” for seriously affecting life qualities of patients. In recent years, the morbidity of IBD has been increasing each year, not only in Western countries but also in developing countries located in South America, Asia, Africa, and Eastern Europe[1]. Cell death is crucial to maintaining homeostasis. More and more researchers pay attention to the role of cell death, especially the death of intestinal epithelial cells (IECs), in the development and progression of IBD. Under normal circumstances, the proliferation and death of intestinal cells, including IECs, Paneth cells, goblet cells, and immune cells, are strictly regulated. Cell death dysregulation leads to the occurrence, aggravation, and maintenance of inflammation, even carcinogenesis.

Necroptosis is a form of programmed cell death studied in the few past decades, and it is clearly distinguished from apoptosis and necrosis. The plasma membrane remains intact in apoptotic cells, preventing the leakage of intracellular contents and making apoptosis “silent” and “safe”. Necrosis causes the release of intracellular contents and an inflammatory response in an uncontrollable manner. Necroptosis induces an inflammatory response in a controllable manner, but still contributes to the progression of inflammation, tumors[2], and infection[3]. This paper reviewed the roles of necroptosis in IBD and explored potential targeting drugs for the treatment of IBD.

1. Necroptosis

1.1. Canonical pathways of necroptosis

Necroptosis is a novel mode of regulatory cell death that was discovered in 1988[4] and named in 2005[5]. Necroptosis is mainly induced by ligands of death receptors such as tumor necrosis factor family receptors (TNFRs), pattern recognition receptors, and virus sensors. Necroptosis causes a series of reactions, including but not limited to receptor interacting protein kinase 1 (RIPK1) and RIPK3 interactions, and ultimately activates mixed lineage kinase domain-like protein (MLKL), which is the executor of necroptosis. MLKL is normally inhibited by its own brace auto-inhibitory helix α6. When phosphorylated, MLKL forms pMLKL with the exposed four-helix bundle, which is activated and directly or indirectly leads to cell swelling, plasma membrane rupture, leakage of intracellular content, and cell death. This process mainly involves RIPK1, RIPK3, and MLKL. The relevant structure can be seen in Figure 1.

Figure 1. Structure diagram of molecules mediating necroptosis.

Figure 1

Open in a new tab

RIPK1 is composed of an N-terminal kinase domain (KD), an intermediate domain (ID), a C-terminal RHIM domain, and a death domain (DD). RIPK3 lacks a C-terminal DD compared with RIPK1. MLKL has an N-terminal four-helix bundle domain. When phosphorylated, MLKL is activated and pMLKL forms, with the exposed four-helix bundle (the green part), arousing necroptosis. RIPK: Receptor interacting protein kinase; RHIM: Receptor-interacting protein kinase homotypic interaction motif; MLKL: Mixed lineage kinase domain-like protein; pMLKL: Phosphorylated MLKL.

The RIPK1-RIPK3-MLKL pathway mediated by TNFR1 is one of the most widely studied pathways. Stimulated by TNF-α, RIPK1, and TNF receptor-related death domain (TRADD) are independently recruited into TNFR1[6-7] through their death domain (DD). Necroptosis is triggered after activation of death domain receptors. Two families with variants in RIPK1 (D324V and D324H) that cannot be cleaved by caspase-8 suffer from an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis[8]. When caspase-8 is deleted or inactivated, RIPK1, RIPK3, and MLKL form necrosomes and induce necroptosis. Other stimulants, including activation of death receptors (TNFR, Fas, and TRAILR)[9], activation of T cell receptors[10], anticancer drugs[11-12], vaccinia infection[13], and respiratory syncytial virus infection[14-15], can also lead to necroptosis via this pathway.

1.2. Non-canonical pathways of necroptosis

Some forms of stimulations induce necroptosis through nonclassical pathways, including the ZBP1/DAI-RIPK3-MLKL pathway, TRIF-RIPK3-MLKL pathway, and high RIPK3-MLKL pathway. The ZBP1/DAI-RIPK3-MLKL pathway exists in cytomegalovirus (CMV) infection[16], influenza A virus (IAV) infection[17], and interferon-induced necroptosis[18]. Activation of Toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) induces necroptosis through the TRIF-RIPK3-MLKL pathway. In the absence of upstream stimulation, high level of RIPK3 may directly activate necroptosis and inflammatory pathways downstream of RIPK3.

2. Necroptosis in IBD

Inflammation in the intestine is characterized by increased death of IECs. When necroptosis, a non-apoptotic programmed cell death, is triggered in the intestinal epithelium, ileal and colonic inflammation would appear in mice[19]. In a dextran sulfate sodium (DSS)-induced colitis model (UC model), the expression of RIPK1 and RIPK3 was upregulated[20-22]. In a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis model (CD model), the number of nonapoptotic dead cells and the level of p-RIPK3 in the intestinal mucosa were increased, suggesting that necroptosis is related to TNBS-induced colitis[23]. In addition, the expression of necroptosis-related proteins (RIPK1, RIPK3, and pMLKL) was increased in the serum of IBD patients[24]. What kinds of roles does necroptosis play in IBD? We mainly discussed the following 4 aspects.

2.1. Necroptosis is involved in the pathogenesis of IBD

The pathogenesis of IBD is related to heredity, intestinal epithelial barrier function, immunity, and environment. Necroptosis contributes to impairing intestinal epithelial integrity, compromised immunity, and the adverse impact of the environment on IBD.

2.1.1. Necroptosis promotes IBD by impairing functions of intestinal epithelial barrier

Necroptosis is negatively correlated with normal functions of the intestinal barrier[25-26]. In the intestinal mucosa of pediatric IBD patients, pMLKL is increased and E-cadherin is reduced. Expression of E-cadherin, Occludin, and Zonulin-1 is increased in DSS-induced colitis after inhibition of RIPK1[27]. Matsuzawa-Ishimoto, et al[28] found that in the intestinal organoids lacking autophagy gene ATG16L1, Paneth cells decrease due to TNF-α-mediated necroptosis. Pathological phenomena caused by impaired functions of the intestinal barrier like increased intestinal permeability, higher incidence of bacterial spreading to the spleens, dysfunctions of junction proteins, and increased level of necroptosis were observed in vivo and in vitro[29-31]. A transgenic mouse model with overexpressed intestinal vitamin D receptors has significantly decreased DSS-induced structural damages and barrier dysfunction by reducing the formation of RIPK1-RIPK3 necrosome[24].

2.1.2. Necroptosis facilitates the development of IBD by regulating immune cells

Necroptosis affects the development of IBD through regulating immune cells. Inhibiting necroptosis can perturb the infiltration of intestinal macrophages and neutrophils, hinder the expression of proinflammatory factors, which significantly reduce DSS-induced colitis in mice[32]. Consistently, inhibiting functions of RIPK1 in mice lowers the infiltration of immunocytes in lamina propria of the colon induced by DSS[27]. In addition, inhibition of RIPK3 ameliorates necroptosis in CD4+T cells and reduces the differentiation of Th17 cells, which can significantly reduce the expression of proinflammatory cytokines and necroptosis in peripheral blood mononuclear cells from UC patients, reduce necroptosis factors and proinflammatory factors in the colon of DSS mice, relieve symptoms of DSS-induced colitis, and protect the intestine[33].

2.1.3. Necroptosis involves in the imbalance of intestinal homeostasis in IBD

Necroptosis is involved in the regulation of intestinal inflammation by mediating the imbalance of intestinal homeostasis. LPS generated from bacteria of crypt-specific core microbiota inhibits cell proliferation and regulates intestinal epithelial cell differentiation by inducing RIPK3-mediated necroptosis via TLR4[34]. Microbiota depletion by antibiotics or gnotobiotics inhibits the expression and activation of RIPK3 and then alleviates the necroptosis of IECs[35]. Knockout of genes regulating circadian rhythm or environmentally induced circadian rhythm disorders increases the susceptibility of mice to severe intestinal inflammation and epithelial disorders, accompanied by excessive necroptosis and a reduced number of secretory epithelial cells[36].

In a nutshell, necroptosis contributes to impairing intestinal epithelial integrity, compromised immunity, and the adverse impact of the environment on IBD, which is mainly worked by impairing functions of intestinal epithelial barrier, regulating immune cells, and mediating the imbalance of intestinal homeostasis.

2.2. Functions of molecules inducing necroptosis in IBD models

2.2.1. RIPK1

Consistent with the above observations, inhibition of RIPK1 blocks necroptosis activation and alleviates DSS-induced colitis[27, 29-30]. RIPK1-deficient mice die of multiple organ inflammation and abnormal cell death at birth[37]. The lethality of RIPK1 deficiency can be prevented by knocking out both the caspase-8 and RIPK3 genes[38-40]. These results suggest that RIPK1 can inhibit excessive cell death, which may include apoptosis and necroptosis, in RIPK1-deficient mice.

2.2.2. RIPK3

Inhibition of RIPK3 alleviates spontaneous colitis in mice with atopic FADD or caspase-8 deletion in the intestinal epithelium[41-42]. This suggests that RIPK3 activation promotes intestinal inflammation. Moriwaki, et al[43] found that RIPK3 (-/-) mice show increased susceptibility to DSS-induced colitis. Xu, et al[44] also found that RIPK3 deficiency aggravates DSS-induced colitis, indicating that targeting RIPK3 can inhibit DSS-induced colitis. However, Newton, et al[45] found that the loss of the RIPK3 gene has no effect on DSS-induced colitis. Generally, in mice with a background inhibiting apoptosis, RIPK3 promotes necroptosis and colitis, while in mice with a background enabling functional apoptosis, RIPK3 can inhibit DSS-induced colitis through its effect on intestinal epithelial repairment. The loss of RIPK3 has no effect on DSS-induced colitis, which may due to the balance between the promotion of necroptosis by RIPK3 and the repair of colonic epithelium.

2.2.3. MLKL

Zhang, et al[46] found that the colitis symptoms of DSS model mice with MLKL deficiency are significantly less severe than those of wild-type mice. However, the magnitude of weight loss and accompanying inflammatory pathology upon MLKL deletion vary substantially between independent repeats[47]. MLKL deficiency can completely prevent the ileitis caused by epithelial caspase-8 knockout[48]. Genetic inhibition of MLKL and necroptosis has a protective effect on enteritis. Animal experiments confirmed that the activation of MLKL and signal transducer and activator of transcription 1 (STAT1) is necessary for the reduction in the number of Paneth cells in the colon of wild-type mice injected with a vector expressing interferon lambda (IFNL)[49].

In general, blocking necroptosis is active in IBD mouse models. The effects of RIPK3 regulation in the IBD model are very complex and are related to the genetic background of the IBD model. Results in the gene MLKL deficient mice remain contradictory.

2.3. Functions of necroptosis in IBD patients

RIPK3 and MLKL are upregulated in inflammatory tissues of UC patients and are positively correlated with UC activity[50]. Guenther, et al[19] found high expression of RIPK3 in Paneth cells and increased necroptosis in terminal ileum cells of CD patient. In addition, the loss of Paneth cells in CD patients is accompanied by increased levels of IFNL in the serum and inflammatory ileum. Roy, et al[51] found that the level of necroptosis in the distal ileum of CD patients is increased. Similar changes are observed in children with IBD. Pierdomenico, et al[52] analyzed ileum and colon samples from 63 patients with IBD, 10 patients with allergic colitis (AC), and 20 healthy children. They found that RIPK3 and MLKL are increased while caspase-8 is decreased in inflammatory tissues from IBD and AC children but not in those from healthy children[52]. The results are consistent with those observed in IBD models.

Cuchet-Lourenco, et al[53] and Li, et al[54] reported 11 patients with biallelic RIPK1 mutations characterized by recurrent infection, early IBD, and progressive polyarthritis. The pathogenesis of these patients was related to defective differentiation of T cells and B cells, increased activity of inflammatory cells, and impaired response of IECs to TNFR1-mediated cell death. One of the patients obtained symptom relief from hematopoietic stem cell transplantation. Recently, a patient with multiple heterozygous mutations of the RIPK1 gene was reported[55], and the patient showed diarrhea, repeated infection, obvious reduction of T, B, NK cells, and immunoglobulin levels. All patients with RIPK1 gene mutations have immune deficiency, early IBD, or diarrhea symptoms. A lack of caspase-8 in the human body is related to immune deficiency or very early IBD[56], which may be treated by targeting RIPK3 or MLKL.

In a word, the level of necroptosis is increased in IBD patients, IBD patients have changed gene profiles of necroptosis, and inhibition of necroptosis may be a potential therapeutic strategy for IBD.

2.4. Functions of necroptosis regulating drugs in IBD models

Because of its excessive activation in IBD animal models and patients, necroptosis is considered as a potential target for therapeutic approaches of IBD. Some necroptosis regulating drugs play an anti-inflammatory role in IBD models and in vitro studies (Table 1).

Table 1.

(to be continued)

Regulating drugs Target Mechanism/measures Studies in vitro or animal models References
M10 (a Myricetin-3-O-b-D-Lactose Sodium Salt) Prevent necroptosis through down-regulating the TNF-α pathway DSS-induced chronic colitis in mice [68]
Open in a new tab

RIP: Receptor interacting protein kinase, the same as RIPK; HMGB1: High mobility group protein 1; pMLKL: Phosphorylated mixed lineage kinase domain-like protein, active form of MLKL; HT-29 cells and Caco-2 cells: Human colorectal cancer cell line; TNF-α + Smac + z-VAD, z-VAD+TNF-α and TNF-α+BV6+Z-VAD: Necroptosis inducers; IBD: Inflammatory bowel disease; UC: Ulcerative colitis; THP-1 cells: Monocyte line of human peripheral blood; Jurkat cells: Isolated from peripheral blood of a boy with T-cell leukemia; pRIPK1: Phosphorylated RIPK1; pRIPK3: Phosphorylated RIPK3; DSS: Dextran sulfate sodium; PBMC: Peripheral blood mononuclear cell; RAW264.7 cells: Mouse monocyte macrophage line; ZO-1: Zonula occludens-1; MUC-2: Mucin2.

Necrostatin-1 is the first compound to be identified as an inhibitor of necroptosis, which targets RIPK1. Necrostatin-1 reduces intestinal inflammation in cultured intestinal explants from IBD[57]. RIPK1 inhibitor GSK2982772 reduces the IL-1β and IL-6 released by cultured intestinal explants from UC patients[58]. Unfortunately, GSK2982772 as monotherapy is not a promising treatment for patients with active UC based on a clinical trial[59]. Other RIPK1 inhibitors like UCF-101 alleviate DSS-induced colitis by preventing necroptosis of IECs[29]. LY3009120 inhibits the infiltration of intestinal macrophages and neutrophils and the expression of pro-inflammatory factors, and significantly relieves DSS-induced colitis.

RIPK3 inhibitors targeting RIPK1 kinase functions include GSK′840, GSK′842, GSK′872, GW′39B, and dabrafenib[60-63]. Among them, GSK′872 reduces the expression of pro-inflammatory cytokines and the level of necroptosis in peripheral blood mononuclear cells from UC patients and the colon of DSS-induced mice[33]. High doses of these drugs can induce RIPK3-dependent apoptosis, which is consistent with the observation of intrauterine death in mice expressing kinase-dead RIPK3[64]. Mice expressing a kinase-dead RIPK3 protein with different point mutations develop normally and survive into adulthood[65], indicating that it is still possible to inhibit RIPK3 kinase activity without inducing apoptosis.

In addition, some drugs inhibiting necroptosis (e.g., neferine, dihydrotanshinone I, hesperetin) have shown therapeutic effects in IBD mouse models, symptom relief, and biochemical changes related to enteritis (Table 1).

Although these drugs have not been enrolled in clinical trials, they show the potential treating IBD and indicate some paths toward curative targeting therapies.

Table 1.

Functions of necroptosis regulating drugs in IBD models

Regulating drugs Target Mechanism/measures Studies in vitro or animal models References
Necrostatin-1 RIPK1

Inhibit the upregulation of RIP1 and RIP3 and enhanced the expression of caspase-8;

Reduce the production of IL-8, IL-1β, IL-6 and release of HMGB1;

Suppressed tumor growth and development through inhibiting JNK/c-Jun signaling;

DSS-induced acute colitis in mice;

HT-29 cells treated with TNF-α + Smac + z-VAD;

Mice treated with AOM+DSS;

 [20]
Inhibit the increasing pMLKL and the activation of cytokines and alarmins, and altering epithelial permeability Cultured intestinal explants from IBD patients [57]
GSK2982772 RIPK1 Reduce spontaneous production of IL-1β and IL-6; Cultured intestinal explants from UC patients; [58]
Reduce tight junctions’ disruption, ameliorate the intestinal barrier injury, suppress the chemokines and adhesion molecules from damaged intestinal epithelial cells (IECs)

DSS-induced colitis model and

HT-29 cells, THP-1 and Jurkat cells

 [27]
UCF-101 RIPK1

Prevent intestinal barrier function loss and inhibited necroptosis of IECs;

Inhibit the increase of pRIPK1, pRIPK3,

pMLKL

DSS-induced acute colitis in mice;

HT-29 and L929 cells treated with TNF-α + Smac + z-VAD

 [29]
LY3009120 RIPK1 Inhibit necroptosis of IECs and prevent intestinal barrier function loss, infiltration of macrophages and neutrophils, inhibit the increased level of TNF-α, IL-6, and IL-1β in colon DSS-induced acute colitis in mice [30]
GSKʹ872 RIPK3

Reduce necroptosis factors and proinflammatory cytokines;

Decrease the expression of IL-17, IL-6, TNF-α

Colon tissues from patients with UC and DSS-induced colitis;

PBMCs from UC patients stimulated by and zVAD+TNF-α

 [33]
NSA/necrosulfonamide MLKL Against intestinal epithelium necroptosis by inhibiting MLKL function TNBS-induced colitis in mice; Caco-2 cells treated with TNF-α+z-VAD [23, 66]
Celastrol Decrease level of RIP3, MLKL, IL-1β, IL-6 and myeloperoxidase, increase level of active caspase-8 DSS-induced acute colitis in mice [67]
Neferine Inhibit the expression of RIPK1, RIPK3, MLKL, induce caspase-8 expression RAW264.7 cells treated with LPS or LPS+Z-VAD; DSS-induced acute colitis in mice [22]
Dihydrotanshinone I

Inhibit the expression and phosphorylation of RIPK1, RIPK3, MLKL;

Induce caspase-8 expression

 DSS-induced acute colitis in mice, RAW264.7 cells treated with LPS or LPS+Z-VAD, HT29 cells treated with TNF-α+BV6+Z-VAD [21]
Hesperetin

Inhibit RIPK3 and MLKL;

Increase ZO-1, occludin, MUC-2, TNF-α, IL-1β, IL-18, HMGB1, and IL-6 expression, and trans epithelial electric resistance

 DSS-induced colitis in mice; cell-coculture system between Caco-2 and RAW264.7 cells stimulated with HS-173 (necroptosis inducer) [31]
Open in a new tab

3. Conclusion

Necroptosis is a novel programmed cell death mainly mediated by RIPK1-RIPK3-MLKL pathway. The level of necroptosis in IBD patients and animal models increases. Necroptosis is involved in the pathogenesis of IBD by impairing functions of the intestinal epithelial barrier, regulating immune cells, and mediating the imbalance of intestinal homeostasis. IBD patients had changed gene profiles of necroptosis, which provides molecular targets for therapeutic strategies in the future.

Pharmacological inhibition of RIPK1, RIPK3, MLKL or the level of necroptosis protects against enteritis. However, because of the complexity of the regulation of necroptosis and the multiple functions of its related signaling molecules, the specific mechanism remains elusive.

Regardless, it is undeniable that necroptosis modulators targeting necroptosis signaling molecules have good therapeutic prospects in the treatment of IBD. More studies on the mechanisms of necroptosis in IBD and clinical trials in necroptosis regulating drugs are expected.

Acknowledgments

We thank all the people who supported our work and who made researches in this area.

Funding Statement

This work was supported by the Natural Science Foundation of Hunan Province (2021JJ31021), the Research Programs of Hunan Hygienism and Health Committee (202103031923), and the Scientific Research Program of Human Administration Bureau of Chinese Medicine (D2022026), China.

Conflict of Interest

The authors declare that they have no conflicts of interest to disclose.

AUTHORS’CONTRIBUTIONS

LONG Xiuyan Collected data, conceptualized the manuscript, drafted, edited and submitted the manuscript; ZHU Ningxin Conceptualized the manuscript, drafted the manuscript, critically reviewed and revised the manuscript; QIU Jianing Collected data, critically reviewed and revised the manuscript; YU Xiaoyu, RUAN Xixian Critically reviewed and revised the manuscript; WANG Xiaoyan Conceptualized the manuscript; TIAN Li Conceptualized the manuscript, reviewed and revised the manuscript. All authors have approved the final version of this manuscript.

Note

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/2022091289.pdf

References

  • 1. Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies[J]. Lancet, 2017, 390(10114): 2769-2778. 10.1016/S0140-6736(17)32448-0. [DOI] [PubMed] [Google Scholar]
  • 2. Hu BW, Shi DY, Lv X, et al. Prognostic and clinicopathological significance of MLKL expression in cancer patients: a meta-analysis[J]. BMC Cancer, 2018, 18(1): 736. 10.1186/s12885-018-4655-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Upton JW, Kaiser WJ, Mocarski ES. Cytomegalovirus M45 cell death suppression requires receptor-interacting protein (RIP) homotypic interaction motif (RHIM)-dependent interaction with RIP1 [J]. J Biol Chem, 2008, 283(25): 16966-16970. 10.1074/jbc.C800051200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Laster SM, Wood JG, Gooding LR. Tumor necrosis factor can induce both apoptic and necrotic forms of cell Lysis[J]. J Immunol, 1988, 141(8): 2629-2634. [PubMed] [Google Scholar]
  • 5. Degterev A, Huang ZH, Boyce M, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury[J]. Nat Chem Biol, 2005, 1(2): 112-119. 10.1038/nchembio711. [DOI] [PubMed] [Google Scholar]
  • 6. Hsu H, Shu HB, Pan MG, et al. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways[J]. Cell, 1996, 84(2): 299-308. 10.1016/s0092-8674(00)80984-8. [DOI] [PubMed] [Google Scholar]
  • 7. Zheng LX, Bidere N, Staudt D, et al. Competitive control of independent programs of tumor necrosis factor receptor-induced cell death by TRADD and RIP1[J]. Mol Cell Biol, 2006, 26(9): 3505-3513. 10.1128/MCB.26.9.3505-3513.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Tao PF, Sun JQ, Wu ZM, et al. A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1[J]. Nature, 2020, 577(7788): 109-114. 10.1038/s41586-019-1830-y. [DOI] [PubMed] [Google Scholar]
  • 9. Holler N, Zaru R, Micheau O, et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule[J]. Nat Immunol, 2000, 1(6): 489-495. 10.1038/82732. [DOI] [PubMed] [Google Scholar]
  • 10. Ch'en IL, Beisner DR, Degterev A, et al. Antigen-mediated T cell expansion regulated by parallel pathways of death[J]. PNAS, 2008, 105(45): 17463-17468. 10.1073/pnas.0808043105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Basit F, Cristofanon S, Fulda S. Obatoclax (GX15-070) triggers necroptosis by promoting the assembly of the necrosome on autophagosomal membranes[J]. Cell Death Differ, 2013, 20(9): 1161-1173. 10.1038/cdd.2013.45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Liu TC, Sun X, Cao ZW. Shikonin-induced necroptosis in nasopharyngeal carcinoma cells via ROS overproduction and upregulation of RIPK1/RIPK3/MLKL expression[J]. Onco-targets Ther, 2019, 12: 2605-2614. 10.2147/ott.s200740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Cho YS, Challa S, Moquin D, et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation[J]. Cell, 2009, 137(6): 1112-1123. 10.1016/j.cell.2009.05.037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Simpson J, Loh Z, Ullah MA, et al. Respiratory syncytial virus infection promotes necroptosis and HMGB1 release by airway epithelial cells[J]. Am J Respir Crit Care Med, 2020, 201(11): 1358-1371. 10.1164/rccm.201906-1149oc. [DOI] [PubMed] [Google Scholar]
  • 15. Santos LD, Antunes KH, Muraro SP, et al. TNF-mediated alveolar macrophage necroptosis drives disease pathogenesis during respiratory syncytial virus infection[J]. Eur Respir J, 2021, 57(6): 2003764. 10.1183/13993003.03764-2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Upton JW, Kaiser WJ, Mocarski ES. Virus inhibition of RIP3-dependent necrosis[J]. Cell Host Microbe, 2010, 7(4): 302-313. 10.1016/j.chom.2010.03.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Zhang T, Yin CR, Boyd DF, et al. Influenza virus Z-RNAs induce ZBP1-mediated necroptosis[J/OL]. Cell, 2020, 180(6): 1115-1129. e13 [2021-02-19]. 10.1016/j.cell.2020.02.050. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Yang DW, Liang YJ, Zhao SB, et al. ZBP1 mediates interferon-induced necroptosis[J]. Cell Mol Immunol, 2020, 17(4): 356-368. 10.1038/s41423-019-0237-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Günther C, Martini E, Wittkopf N, et al. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis[J]. Nature, 2011, 477(7364): 335-339. 10.1038/nature10400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Liu ZY, Wu B, Guo YS, et al. Necrostatin-1 reduces intestinal inflammation and colitis-associated tumorigenesis in mice[J]. Am J Cancer Res, 2015, 5(10): 3174-3185. [PMC free article] [PubMed] [Google Scholar]
  • 21. Guo YL, Wu XX, Wu Q, et al. Dihydrotanshinone I, a natural product, ameliorates DSS-induced experimental ulcerative colitis in mice[J]. Toxicol Appl Pharmacol, 2018, 344: 35-45. 10.1016/j.taap.2018.02.018. [DOI] [PubMed] [Google Scholar]
  • 22. Wu XX, Guo YL, Min XJ, et al. Neferine, a bisbenzy-lisoquinoline alkaloid, ameliorates dextran sulfate sodium-induced ulcerative colitis[J]. Am J Chin Med, 2018, 46(6): 1263-1279. 10.1142/s0192415x18500660. [DOI] [PubMed] [Google Scholar]
  • 23. Dong W, Zhang M, Zhu YX, et al. Protective effect of NSA on intestinal epithelial cells in a necroptosis model[J]. Oncotarget, 2017, 8(49): 86726-86735. 10.18632/oncotarget.21418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Shi YY, Cui XW, Sun YL, et al. Intestinal vitamin D receptor signaling ameliorates dextran sulfate sodium-induced colitis by suppressing necroptosis of intestinal epithelial cells[J]. FASEB J, 2020, 34(10): 13494-13506. 10.1096/fj.202000143RRR. [DOI] [PubMed] [Google Scholar]
  • 25. Lou XH, Zhu HT, Ning LG, et al. EZH2 regulates intestinal inflammation and necroptosis through the JNK signaling pathway in intestinal epithelial cells[J]. Dig Dis Sci, 2019, 64(12): 3518-3527. 10.1007/s10620-019-05705-4. [DOI] [PubMed] [Google Scholar]
  • 26. Wang RC, Li HD, Wu JF, et al. Gut stem cell necroptosis by genome instability triggers bowel inflammation[J]. Nature, 2020, 580(7803): 386-390. 10.1038/s41586-020-2127-x. [DOI] [PubMed] [Google Scholar]
  • 27. Lu HM, Li H, Fan C, et al. RIPK1 inhibitor ameliorates colitis by directly maintaining intestinal barrier homeostasis and regulating following IECs-immuno crosstalk[J]. Biochem Pharmacol, 2020, 172: 113751. 10.1016/j.bcp.2019.113751. [DOI] [PubMed] [Google Scholar]
  • 28. Matsuzawa-Ishimoto Y, Shono Y, Gomez LE, et al. Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium[J]. J Exp Med, 2017, 214(12): 3687-3705. 10.1084/jem.20170558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Zhang C, He AD, Liu S, et al. Inhibition of HtrA2 alleviated dextran sulfate sodium (DSS)-induced colitis by preventing necroptosis of intestinal epithelial cells[J]. Cell Death Dis, 2019, 10(5): 344. 10.1038/s41419-019-1580-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Zhang C, Luo YQ, He QL, et al. A pan-RAF inhibitor LY3009120 inhibits necroptosis by preventing phosphorylation of RIPK1 and alleviates dextran sulfate sodium-induced colitis[J]. Clin Sci (Lond), 2019, 133(8): 919-932. 10.1042/CS20181081. [DOI] [PubMed] [Google Scholar]
  • 31. Zhang JX, Lei HB, Hu X, et al. Hesperetin ameliorates DSS-induced colitis by maintaining the epithelial barrier via blocking RIPK3/MLKL necroptosis signaling[J]. Eur J Pharmacol, 2020, 873: 172992. 10.1016/j.ejphar.2020.172992. [DOI] [PubMed] [Google Scholar]
  • 32. Zhang C, He AD, Liu S, et al. Inhibition of HtrA2 alleviated dextran sulfate sodium (DSS)-induced colitis by preventing necroptosis of intestinal epithelial cells[J]. Cell Death Dis, 2019, 10(5): 344. 10.1038/s41419-019-1580-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Lee SH, Kwon JY, Moon J, et al. Inhibition of RIPK3 pathway attenuates intestinal inflammation and cell death of inflammatory bowel disease and suppresses necroptosis in peripheral mononuclear cells of ulcerative colitis patients[J/OL]. Immune Netw, 2020, 20(2): e16 [2021-03-14]. 10.4110/in.2020.20.e16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Naito T, Mulet C, de Castro C, et al. Lipopolysaccharide from crypt-specific core microbiota modulates the colonic epithelial proliferation-to-differentiation balance[J/OL]. mBio, 2017, 8(5): e01680-17 [2019-07-23]. 10.1128/mbio.01680-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Xie YD, Zhao YF, Shi L, et al. Gut epithelial TSC1/mTOR controls RIPK3-dependent necroptosis in intestinal inflammation and cancer[J]. J Clin Investig, 2020, 130(4): 2111-2128. 10.1172/jci133264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Pagel R, Bär F, Schröder T, et al. Circadian rhythm disruption impairs tissue homeostasis and exacerbates chronic inflammation in the intestine[J]. FASEB J, 2017, 31(11): 4707-4719. 10.1096/fj.201700141RR. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Kelliher MA, Grimm S, Ishida Y, et al. The death domain kinase RIP mediates the TNF-induced NF-kappaB signal[J]. Immunity, 1998, 8(3): 297-303. 10.1016/s1074-7613(00)80535-x. [DOI] [PubMed] [Google Scholar]
  • 38. Dillon CP, Weinlich R, Rodriguez DA, et al. RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3[J]. Cell, 2014, 157(5): 1189-1202. 10.1016/j.cell.2014.04.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Rickard JA, O'Donnell JA, Evans JM, et al. RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis[J]. Cell, 2014, 157(5): 1175-1188. 10.1016/j.cell.2014.04.019. [DOI] [PubMed] [Google Scholar]
  • 40. Kaiser WJ, Daley-Bauer LP, Thapa RJ, et al. RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition[J]. Proc Natl Acad Sci USA, 2014, 111(21): 7753-7758. 10.1073/pnas.1401857111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Günther C, Buchen B, He GW, et al. Caspase-8 controls the gut response to microbial challenges by Tnf-α-dependent and independent pathways[J]. Gut, 2015, 64(4): 601-610. 10.1136/gutjnl-2014-307226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. Weinlich R, Oberst A, Dillon CP, et al. Protective roles for caspase-8 and cFLIP in adult homeostasis[J]. Cell Rep, 2013, 5(2): 340-348. 10.1016/j.celrep.2013.08.045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Moriwaki K, Balaji S, McQuade T, et al. The necroptosis adaptor RIPK3 promotes injury-induced cytokine expression and tissue repair[J]. Immunity, 2014, 41(4): 567-578. 10.1016/j.immuni.2014.09.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Xu YL, Tang HL, Zhu SY, et al. RIP3 deficiency exacerbates inflammation in dextran sodium sulfate-induced ulcerative colitis mice model[J]. Cell Biochem Funct, 2017, 35(3): 156-163. 10.1002/cbf.3257. [DOI] [PubMed] [Google Scholar]
  • 45. Newton K, Dugger DL, Maltzman A, et al. RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury[J]. Cell Death Differ, 2016, 23(9): 1565-1576. 10.1038/cdd.2016.46. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. Zhang J, Qin D, Yang YJ, et al. MLKL deficiency inhibits DSS-induced colitis independent of intestinal microbiota[J]. Mol Immunol, 2019, 107: 132-141. 10.1016/j.molimm.2019.01.018. [DOI] [PubMed] [Google Scholar]
  • 47. Alvarez-Diaz S, Preaudet A, Samson AL, et al. Necroptosis is dispensable for the development of inflammation-associated or sporadic colon cancer in mice[J]. Cell Death Differ, 2021, 28(5): 1466-1476. 10.1038/s41418-020-00673-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Schwarzer R, Jiao HP, Wachsmuth L, et al. FADD and caspase-8 regulate gut homeostasis and inflammation by controlling MLKL- and GSDMD-mediated death of intestinal epithelial cells[J]. Immunity, 2020, 52(6): 978-993. 10.1016/j.immuni.2020.04.002. [DOI] [PubMed] [Google Scholar]
  • 49. Günther C, Ruder B, Stolzer I, et al. Interferon lambda promotes paneth cell death via STAT1 signaling in mice and is increased in inflamed ileal tissues of patients with Crohn’s disease[J/OL]. Gastroenterology, 2019, 157(5): 1310-1322. e13 [2020-03-01]. 10.1053/j.gastro.2019.07.031. [DOI] [PubMed] [Google Scholar]
  • 50. Wu TL, Dai YY, Xue LL, et al. Expression of receptor interacting protein 3 and mixed lineage kinase domain-like protein-key proteins in necroptosis is upregulated in ulcerative colitis[J]. Ann Palliat Med, 2019, 8(4): 483-489. 10.21037/apm.2019.07.04. [DOI] [PubMed] [Google Scholar]
  • 51. Roy S, Esmaeilniakooshkghazi A, Patnaik S, et al. Villin-1 and gelsolin regulate changes in actin dynamics that affect cell survival signaling pathways and intestinal inflammation[J/OL]. Gastroenterology, 2018, 154(5): 1405-1420. e2 [2020-01-11]. 10.1053/j.gastro.2017.12.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52. Pierdomenico M, Negroni A, Stronati L, et al. Necroptosis is active in children with inflammatory bowel disease and contributes to heighten intestinal inflammation[J]. Am J Gastroenterol, 2014, 109(2): 279-287. 10.1038/ajg.2013.403. [DOI] [PubMed] [Google Scholar]
  • 53. Cuchet-Lourenço D, Eletto D, Wu CX, et al. Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation[J]. Science, 2018, 361(6404): 810-813. 10.1126/science.aar2641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. Li Y, Führer M, Bahrami E, et al. Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases[J]. Proc Natl Acad Sci USA, 2019, 116(3): 970-975. 10.1073/pnas.1813582116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55. Lin L, Wang Y, Liu LY, et al. Clinical phenotype of a Chinese patient with RIPK1 deficiency due to novel mutation[J]. Genes Dis, 2019, 7(1): 122-127. 10.1016/j.gendis.2019.10.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. Lehle AS, Farin HF, Marquardt B, et al. Intestinal inflammation and dysregulated immunity in patients with inherited caspase-8 deficiency[J]. Gastroenterology, 2019, 156(1): 275-278. 10.1053/j.gastro.2018.09.041. [DOI] [PubMed] [Google Scholar]
  • 57. Negroni A, Colantoni E, Pierdomenico M, et al. RIP3 and pMLKL promote necroptosis-induced inflammation and alter membrane permeability in intestinal epithelial cells[J]. Dig Liver Dis, 2017, 49(11): 1201-1210. 10.1016/j.dld.2017.08.017. [DOI] [PubMed] [Google Scholar]
  • 58. Harris PA, Berger SB, Jeong JU, et al. Discovery of a first-in-class receptor interacting protein 1 (RIP1) kinase specific clinical candidate (GSK2982772) for the treatment of inflammatory diseases[J]. J Med Chem, 2017, 60(4): 1247-1261. 10.1021/acs.jmedchem.6b01751. [DOI] [PubMed] [Google Scholar]
  • 59. Weisel K, Scott N, Berger S, et al. A randomised, placebo-controlled study of RIPK1 inhibitor GSK2982772 in patients with active ulcerative colitis[J/OL]. BMJ Open Gastroenterol, 2021, 8(1): e000680 [2021-08-14]. 10.1136/bmjgast-2021-000680. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60. Kaiser WJ, Sridharan H, Huang CZ, et al. Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL[J]. J Biol Chem, 2013, 288(43): 31268-31279. 10.1074/jbc.M113.462341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61. Dondelinger Y, Declercq W, Montessuit S, et al. MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates[J]. Cell Rep, 2014, 7(4): 971-981. 10.1016/j.celrep.2014.04.026. [DOI] [PubMed] [Google Scholar]
  • 62. Rodriguez DA, Weinlich R, Brown S, et al. Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis[J]. Cell Death Differ, 2016, 23(1): 76-88. 10.1038/cdd.2015.70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Li JX, Feng JM, Wang Y, et al. The B-Raf(V600E) inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen-induced liver injury[J/OL]. Cell Death Dis, 2014, 5(6): e1278 [2019-05-17]. 10.1038/cddis.2014.241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Newton K, Dugger DL, Wickliffe KE, et al. Activity of protein kinase RIPK3 determines whether cells Die by necroptosis or apoptosis[J]. Science, 2014, 343(6177): 1357-1360. 10.1126/science.1249361. [DOI] [PubMed] [Google Scholar]
  • 65. Mandal P, Berger SB, Pillay S, et al. RIP3 induces apoptosis independent of pronecrotic kinase activity[J]. Mol Cell, 2014, 56(4): 481-495. 10.1016/j.molcel.2014.10.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66. Sun LM, Wang HY, Wang ZG, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase[J]. Cell, 2012, 148(1/2): 213-227. 10.1016/j.cell.2011.11.031. [DOI] [PubMed] [Google Scholar]
  • 67. Jia ZY, Xu CF, Shen JQ, et al. The natural compound celastrol inhibits necroptosis and alleviates ulcerative colitis in mice[J]. Int Immunopharmacol, 2015, 29(2): 552-559. 10.1016/j.intimp.2015.09.029. [DOI] [PubMed] [Google Scholar]
  • 68. Zhou XL, Yang J, Qu XJ, et al. M10, a myricetin-3-O-b-D-lactose sodium salt, prevents ulcerative colitis through inhibiting necroptosis in mice[J]. Front Pharmacol, 2020, 11: 557312. 10.3389/fphar.2020.557312. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Central South University Medical Sciences are provided here courtesy of Central South University

RESOURCES