Abstract
Interferon Gamma Inducible Protein 16 (IFI16) belongs to the HIN-200 protein family and is pivotal in immunological responses. Serving as a DNA sensor, IFI16 identifies viral and aberrant DNA, triggering immune and inflammatory responses. It is implicated in diverse cellular death mechanisms, such as pyroptosis, apoptosis, and necroptosis. Notably, these processes are integral to the emergent concept of PANoptosis, which encompasses cellular demise and inflammatory pathways. Current research implies a significant regulatory role for IFI16 in PANoptosis, particularly regarding cardiac pathologies. This review delves into the complex interplay between IFI16 and PANoptosis in heart diseases, including atherosclerosis, myocardial infarction, heart failure, and diabetic cardiomyopathy. It synthesizes evidence of IFI16’s impact on PANoptosis, with the intention of providing novel insights for therapeutic strategies targeting heart diseases.
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Facts
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Pyroptosis, apoptosis, and/or necroptosis by themselves are insufficient to describe PANoptosis, an inflammatory form of programmed cell death mediated by the PANoptosome complex.
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IFI16 and AIM2 are HIN-200 family members that show many of the same functions in biological processes. It has been confirmed that AIM2 plays a central role in PANoptosis. IFI16 is connected to apoptosis and pyroptosis and also has a high expression in STAT3β overexpression cells to enhance necroptosis.
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PANoptosis is involved in heart failure, cancer, sepsis, pulmonary diseases, infectious disease, and so on.
Open questions
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What is the specific role of IFI16 in the PANoptosis progress?
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How does PANoptosis affect heart disease?
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If we intervene in the PANoptosis progress by regulating IFI16, is it possible to prevent and treat heart diseases?
Introduction
The Interferon Gamma Inducible Protein 16 (IFI16), a member of the hematopoietic interferon-inducible nuclear (HIN)-200 family, stands as a sentinel at the intersection of immunity [1], inflammation [2], and cell fate decisions [3, 4]. Within the intricate landscape of the immune system, IFI16 has emerged as a multifunctional player with the ability to sense DNA damage, detect viral threats, and regulate inflammatory responses. Its role in orchestrating these processes has led researchers to explore its potential involvement in various disease contexts [5,6,7]. The significance of various interferon-inducing DNA receptors lies in their capacity to initiate a cascade of immune responses and cellular pathways in response to stressors, ultimately influencing disease outcomes [8]. Its interactions with inflammasome assembly, cytokine release, and cell death pathways are particularly intriguing. This review delves into the emerging understanding of the potential role of IFI16 in heart diseases, with a specific focus on its intricate relationship with PANoptosis – a newly recognized form of pro-inflammatory programmed cell death encompassing the simultaneous activation of pyroptosis, apoptosis, and/or necroptosis, but that cannot be accounted for by any of these three programmed cell death pathways alone [9,10,11].
Central to this review is the concept of PANoptosis – a phenomenon that weaves together different cell death pathways in a synchronized symphony of cellular responses. PANoptosis is an inflammatory programmed cell death that is mediated by the PANoptosome complex and cannot be characterized by pyroptosis, apoptosis, or necroptosis alone [9]. There are four members IFI16, absent in melanoma 2 (AIM2), IFIX, and myeloid cell nuclear differentiation antigen in the HIN-200 family. Only IFI16 and AIM2 can activate the inflammasome [12, 13]. AIM2 and IFI16 have also shown the other same features, such as cytosolic dsDNA sensors, ASC (apoptosis-associated speck-like protein containing a CARD)-dependent inflammasomes, regulating atherosclerosis, autoimmunity, tumorigenesis, and normal neuronal development [1, 14,15,16,17,18,19]. However, research shows that IFI16-β, a human mRNA variation of IFI16, inhibits the AIM2 inflammasome [20]. Furthermore, since AIM2 and IFI16 cannot be substituted, they must have different characteristics [21]. The ways in which a host uses AIM2 and IFI16 in diverse ways to fight infections require further explanation. As research highlights the interactions of IFI16 with pyroptosis [4, 22], apoptosis [23,
Cell death pathways and panoptosis
Cell death, a fundamental biological process, can occur through various distinct pathways, each contributing to diverse physiological and pathological contexts. Three primary cell death pathways are widely recognized: pyroptosis, apoptosis, and necroptosis [46].
Pyroptosis is an inflammatory form of cell death that plays a pivotal role in host defense against infections. It is characterized by cell swelling, plasma membrane rupture, and the release of pro-inflammatory cytokines [47]. Activation of pyroptosis typically involves the assembly of inflammasomes, protein complexes that include caspase-1 [ Heart diseases encompass a spectrum of conditions affecting the heart and blood vessels. In 2020, the crude prevalence of heart diseases is 607.64 million cases and 19.05 million deaths are estimated globally, attributed to various risk factors such as hypertension, dyslipidemia, smoking, and diabetes [69]. Pathophysiologically, heart diseases often involve chronic inflammation [70], endothelial dysfunction [71], oxidative stress [72], and cell death [73] contributing to disease progression. Mechanisms of PANoptosis in heart disease are shown in Fig. 2. Atherosclerosis is a disorder that causes plaque to accumulate in the arteries and is a significant risk factor for heart problems. An essential part of the development of atherosclerotic plaque is the involvement of inflammatory processes in the arterial wall [74] (details in Table 1). Pro-inflammatory cytokines including IL-18, IL-1β, and monocyte chemoattractant protein-1 are released during the process of pyroptosis [75]. These cytokines accelerate the development and instability of atherosclerotic plaques [76, 77]. Multiprotein complexes called inflammasomes are essential for the start of pyroptosis. Additionally, they are connected to the inflammatory process in atherosclerotic plaques [78]. Plaque inflammation is made worse by the activation of inflammasomes in macrophages and endothelial cells inside the plaque, which results in the production of pro-inflammatory cytokines. One important effector molecule in pyroptosis is gasdermin D (GSDMD). Furthermore, new information indicates that the GSDMD and GSDME proteins—which create holes in the membranes of mitochondria and plasma—are essential to the pyroptosis process [79]. In addition to promoting the production of pro-inflammatory cytokines, these proteins cause mitochondrial malfunction and heighten the pro-inflammatory response in atherosclerosis. Gaining insight into these molecular pathways paves the way for therapeutic targeting of pyroptosis to control inflammation and may be slow down the course of AS [80]. Oxidized low-density lipoprotein (LDL) cholesterol may leak out of atherosclerotic plaques when macrophages undergo pyroptosis [81]. This released cholesterol has the potential to worsen lipid buildup in the artery wall, causing oxidative stress [82] and extending the cycle of inflammation and plaque formation [83]. Endothelial cell pyroptosis also weakens the vascular wall’s structural integrity and increases the risk of thrombosis and plaque rupture [84]. Apoptosis may facilitate macrophage removal from atherosclerotic plaques. As a result of their ability to consume fats and produce foam cells, macrophages are essential to the development of atherosclerosis [85]. These foam cells may undergo apoptosis and contribute to the necrotic cores of atherosclerotic plaques [86]. In atherosclerotic lesions, vascular smooth muscle cells also go through apoptosis. This may weaken a plaque’s fibrous cap and increase the likelihood of a rupture [135]. This suggests that the dysregulation of PANoptosis could contribute to the development and progression of HF, offering new avenues for treatment and management of this complex condition. DCM is a complicated syndrome defined by myocardial dysfunction in the absence of coronary artery disease and hypertension. It is associated with metabolic problems such as glucose toxicity and lipotoxicity as a result of insulin resistance. Capillary injury, cardiac fibrosis, and hypertrophy with mitochondrial dysfunction are all important characteristics. Increased oxidative stress and inflammation also contribute to the advancement of DCM. Current treatments are aimed at treating these metabolic anomalies, but new focused therapeutics are required [136] (details in Table 4). Pyroptosis is a specific type of programmed cell death that has been the subject of growing amounts of recent study in the field of DCM. Numerous biological pathways and possible therapeutic targets in this field have been identified by studies. The cGAS-STING signaling pathway, which is active in diabetic hearts, has been the focus of one line of research. Targeting this route may help reduce ventricular dysfunction in DCM since it triggers NLRP3 inflammasome activation, cardiac pyroptosis, and persistent inflammation [137]. An additional investigation emphasized the significance of epigenetic control in pyroptosis, with a specific emphasis on METTL14-mediated m6A methylation of the TINCR lncRNA, which is pivotal in inhibiting pyroptosis and the advancement of DCM [138]. Furthermore, research on the therapeutic potential of hydrogen treatment for DCM has been conducted. It was discovered that inhaling hydrogen reduced pyroptosis and fibrosis, attenuating DCM and suggesting a new course of therapy [Proposing future research directions Subsequent investigations ought to examine the molecular intricacies of IFI16’s involvement in PANoptosis in heart diseases. This includes: Clarifying how IFI16 interacts with certain inflammatory mediators during cardiac stress and charting the cellular consequences that follow. Examining the manipulation of IFI16’s activity as a potential therapeutic approach, such as employing small molecule inhibitors, may help lessen pathologic cell death in long-term ailments like HF. Analyzing the expression patterns of IFI16 at various cardiac disease stages and severity levels may provide prognostic indicators or treatment windows. Investigating IFI16’s function in post-injury cardiac remodeling may lead to the development of fresh tactics for halting maladaptive fibrosis and preserving heart function. A complete knowledge of IFI16’s downstream pathways is necessary to develop treatments that target it; these may include innovative drug delivery methods or gene therapy techniques to alter IFI16’s expression or activity in cardiac tissues. The complex biology of heart disease can be better understood by utilizing IFI16’s role in PANoptosis pathways. It might be a target for therapeutic intervention due to its dual function in controlling inflammation and cell death. The current study supports a new paradigm in therapeutic approaches by highlighting the significance of IFI16 in cardiac diseases. We have the chance to develop novel approaches that might significantly change the therapeutic management of cardiac disease by focusing on IFI16-mediated pathways, providing hope for better patient outcomes and quality of life.Panoptosome in heart diseases
Atherosclerosis
Diabetic cardiomyopathy (DCM)
Conclusion
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Acknowledgements
We apologize to our colleagues in the field whose work could not be included due to space limitations. We thank all members of the Cardiology Department of Longhua Hospital affiliated to the Shanghai University of Traditional Chinese Medicine for their comments and suggestions during the development of this manuscript.
Funding
National Natural Science Foundation to YRW [grant number 82204849], to PL[grant number 82074200]; Traditional Chinese Medicine Research Project of Shanghai Municipal Health Commission to YRW [grant number 2022QN056]; “Clinical research-oriented talents training program” in the Affiliated Hospital of Shanghai University of Traditional Chinese Medicine to YRW [No. 2023LCRC01]; Clinical Technology Innovation Cultivation Program of Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine to YRW [No. PY2022008]; Regional Medical Centre of Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine to YRW [No. ZYZK001-029].
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YR Wang and P Liu conceived and designed the review. XD Chang and B Wang wrote the manuscript. YL Zhao drawn pictures and tables. B Deng, YR Wang, and P Liu reviewed the paper and provided comments. All authors contributed to this manuscript and approved the submitted version.
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Chang, X., Wang, B., Zhao, Y. et al. The role of IFI16 in regulating PANoptosis and implication in heart diseases. Cell Death Discov. 10, 204 (2024). https://doi.org/10.1038/s41420-024-01978-5
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DOI: https://doi.org/10.1038/s41420-024-01978-5
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