|Ahead of print publication
Emerging role of the itaconate-mediated rescue of cellular metabolic stress
Der-Shan Sun, Hsin-Hou Chang
Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan
|Date of Submission||23-Mar-2021|
|Date of Decision||23-Apr-2021|
|Date of Acceptance||14-May-2021|
|Date of Web Publication||01-Sep-2021|
Department of Molecular Biology and Human Genetics, Tzu Chi University, 701, Zhongyang Road, Section 3, Hualien
Source of Support: None, Conflict of Interest: None
Metabolic regulations play vital roles on maintaining the homeostasis of our body. Evidence have suggested that ATF3 and nuclear factor erythroid 2–related factor 2 (NRF2) are critical for maintaining cell function, metabolism, and inflammation/anti-inflammation regulations when cells are under stress, while the upstream regulators in the stressed cells remain elusive. Recent findings have shown that tricarboxylic acid cycle metabolites such as itaconate and succinate are not just mitochondrial metabolites, but rather important signaling mediators, involving in the regulations of metabolism, immune modulation. Itaconate exerts anti-inflammatory role through regulating ATF3 and NRF2 pathways under stressed conditions. In addition, itaconate inhibits succinate dehydrogenase, succinate oxidation and thus blocking succinate-mediated inflammatory processes. These findings suggest itaconate-ATF3 and itaconate-NRF2 axes are well-coordinated machineries that facilitate the rescue against cellular stress. Here, we review these fascinating discoveries, a research field may help the development of more effective therapeutic approach to manage stress-induced inflammation, tissue damage, and metabolic disorder.
Keywords: ATF3, Inflammasome, Itaconate, Mitochondrial stress, Nuclear factor erythroid 2–related factor 2
| Itaconate is a metabolite conducting cellular signaling and modulating immune response|| |
To release energy through the oxidation of organic compounds, the tricarboxylic acid (TCA) cycle (also known as citric acid cycle or Krebs cycle), is a series of chemical reactions involving metabolites with cellular signaling properties . Those microRNAs regulating the metabolic pathways are thus influence the inflammation outcomes . TCA cycle metabolites, including itaconate, succinate, α-ketoglutarate, 2-hydroxyglutarate, fumarate, were shown to exert various cellular signaling properties,,,,,,,. Among these, itaconate, a metabolite with anti-inflammatory property, is derived from the decarboxylation of TCA cycle intermediate cis-aconitate . The immune-responsive gene 1 protein (IRG1) is the enzyme responsible for itaconate production. Lipopolysaccharide (LPS) induces IRG1 to result the accumulation of itaconate, which subsequently reduces interleukin (IL)-1β production . IRG1 deficiency in mice led to the elevation of pro-inflammatory cytokines interleukin (IL)-1β, IL-18, IL-6, IL-12 production during macrophage activation by LPS treatments . IRG1 deficiency also led to increased mortality and lung inflammation in a mouse model of Mycobacterium tuberculosis infection . These results suggest that itaconate is critical infection-induced feedback regulating factor that limits excessive inflammation. Itaconate derivatives, such as 4-Octyl itaconate (4-OI), inhibit aerobic glycolysis by targeting glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase, interferon and inflammasome to exert anti-inflammatory effects,. Overall, these studies highlight that itaconate is not just a mitochondria metabolite but rather an important signaling molecule involved in the regulations of metabolism, immune modulation, and gene expression [Figure 1],,,,,,,.
|Figure 1: Itaconate-induced cell protective anti-stress responses. Inflammatory stimulus such as LPS upregulates the expression of CAD (also known as IRG1), an enzyme converts cis-aconitate to itaconate in the mitochondria . LPS-induced cellular activation leads to glycolytic flux and the transition towards an anaplerotic TCA cycle with high production levels of itaconate . High itaconate levels suppress SDH, blocking succinate-mediated inflammatory processes and inducing the anti-inflammatory proteins NRF2 and cyclic ATF3 . Succinate may enhance proinflammatory cytokine IL-1β pathway through SUCNR1 . Those blue labels indicate the anti-inflammatory and anti-oxidative-stress responses; those red labels indicate proinflammatory responses. LPS: Lipopolysaccharide, CAD: Cis-aconitate decarboxylase, IRG1: Immune-responsive gene 1, SDH: Succinate dehydrogenase, NRF2: Nuclear factor erythroid 2-related factor 2, ARF3: AMP-dependent transcription factor 3, SUCNR1: Succinate receptor 1, IDH: Isocitrate dehydrogenase|
Click here to view
| Anti-inflammatory effects of itaconate derivatives|| |
Anti-inflammatory effects of itaconate have been associated with inhibition succinate dehydrogenase (SDH) [Figure 1],, and down-regulation of inflammasome and pro-inflammatory cytokines,. The 4-OI is a most studied itaconate derivative, displaying anti-inflammatory effects,,. For example, 4-OI reduced the activity of pro-inflammatory cytokine IL-1β in LPS-treated mouse and human macrophages and rescued LPS injection-induced mortality in mice . Treatments of 4-OI ameliorated LPS-stimulated pro-inflammatory cytokines IL-1β, IL-6, and tumor necrosis factor (TNF)-α production in human peripheral blood mononuclear cells (PBMCs) and THP-1 macrophages is associated with the activation of the nuclear factor erythroid 2–related factor 2 (NRF2) pathway . Such 4-OI-mediated NRF2–dependent anti-inflammation can also limit the expression of type I interferon (IFN) . These results collectively suggested that itaconate is an anti-inflammatory metabolite. In addition to 4-OI, some other itaconate derivatives were found to have more or less anti-inflammatory and immune-modulating effects. For example, evidence have shown that both dimethyl itaconate and 4-octyl itaconate induce immunosuppressive phenotypes in an NRF2-independent manner, which associated with inhibited IκBζ and pro-interleukin (IL)-1β induction, as well as pro-inflammatory cytokines IL-6, and interferon-β secretion .
| Itaconate-induced anti-inflammatory ATF3 pathway|| |
Recently, it is shown that itaconate conducts anti-inflammatory effects primarily mediating through at least 3 downstream pathways: Pathway 1, Cyclic AMP-dependent transcription factor (ATF3); pathway 2, NRF2 ; pathway 3, itaconate-mediated inhibition on inflammasome-IL-1 axis .
ATF3 is an anti-inflammatory, basic region-leucine zipper (bZip) DNA binding domain containing transcription factors . By forming dimers with ATF3-itself and various other bZip proteins, such as ATF2, c-Jun, JunB, and JunD, ATF3 can function as a transcriptional activator or repressor,. Evidence have suggested that ATF3 plays a role in a variety of biological processes, such as metabolism,, cell motility , cell cycle , DNA repair , cell death , and various functions on maintaining the homeostasis,,,,,,,,,,,. ATF3 can be up-regulated by stimulations from wide spectrum of toll-like receptors (TLRs), including TLR4, 2/6, 3, 5, 7, and 9, and serves as a negative feedback regulator . For example, ATF3 limits the release of pro-inflammatory cytokine high mobility group box 1, which results in lung injury after LPS challenge . ATF3 also limits LPS-induced chemokine (C-X-C motif) ligand 1 production in mouse airways . Basal and LPS-stimulated chemokine (C-C motif) ligand 4 (CCL4) mRNA and protein levels are higher in the bone-marrow-derived macrophages (BMDMs) of ATF3 deficient (ATF3−/−) mice compared with those of wild type (ATF3+/+) mice . Consistently, primary macrophages from ATF3−/− mice exhibit increased production of IL-6 and IL-12p40 cytokines following TLR activation ; LPS induces higher IL-6 and IL-12 mRNA levels in BMDMs of ATF3−/− mice . Such anti-inflammatory effect of ATF3 is in part mediating through the interact with histone deacetylase 1, leading to histone deacetylation and suppression of IL-6 and IL-12b promoter activity in LPS-treated macrophages . Accordingly, ATF3 was suggested negatively regulating the gene expression of those pr-oinflammatory cytokines containing ATF/CREB binding sites . Additionally, comparisons of wild type and gene knockout mice, evidence have shown that dimethyl itaconate (DI) inhibits LPS-mediated IκBζ induction in mouse BMDMs and ameliorates IL-17-mediated IκBζ induction, and associated psoriatic pathology in mice in an ATF3-dependent but NRF2-independent manner . These results revealed that the itaconate-ATF3 axis exerts an anti-inflammatory role.
In addition to inflammation, mitochondrial stress also induces ATF3 expression . ATF3 was shown to involve in adipocyte hypoxia-mediated mitochondrial regulation . Inhibition of ATF3 expression increased mitochondrial stress and induced cytochrome C release . In addition, ATF3 suppresses PTEN-induced putative kinase 1 gene expression in lung epithelial cells to control mitochondrial homeostasis . In other words, itaconate is a native ATF3 inducer, which couples to metabolic regulation.
| Itaconate and nuclear factor erythroid 2–related factor 2 pathway|| |
NRF2 is an anti-oxidative stress and anti-inflammatory, bZip DNA binding domain-containing transcription factor . Itaconate is transported from the mitochondria to the cytoplasm, where it shows its functions via the carriers that transport dicarboxylate and citrate . In the cytosol, itaconate uses its electrophilic α,β-unsaturated carboxylic acid to alkylate the cysteine residues on Kelch-like ECH-associated protein-1 (KEAP1) that normally binds and promotes proteasome degradation of NRF2 . Similar to the modification of cysteines by fumarate itaconate activates NRF2 by alkylation of KEAP1 cysteine residues. Because 4-OI stabilized V5-tagged NRF2 (NRF2–V5) in COS1 cells co-expressing wild-type KEAP1 but not a cysteine 151 (Cys151)-Ser mutant, Cys151 is a sensor on KEAP1 for itaconate . KEAP1 alkylation allows newly synthesized NRF2 to accumulate and translocate into the nucleus to activate the anti-oxidant and anti-inflammatory gene expression . Accordingly, itaconate is a native NRF2 inducer, which couples to metabolic regulation. By binding to the promoters, NRF2 inhibits the expression of pro-inflammatory genes IL-1β and IL-6 . Similarly, the itaconate derivative 4-OI activates NRF2 signaling to inhibit pro-inflammatory cytokine production in PBMCs .
| Itaconate and succinate-inflammasome-il-1 axis|| |
Immune system defenses against external stimulations and pathogen invasions,,,,,,,,,, in which the inflammasome-IL-1 axis exerts critical role on the induction of inflammation in various conditions,,,,,,,,,,,,. Itaconate was demonstrated to inhibit SDH, and subsequently succinate oxidation and thus blocking succinate-mediated inflammatory processes,. Succinate was shown to induced the pro-inflammatory IL-1 pathway through succinate receptor 1 . By contrast, itaconate and 4-OI specifically inhibited NLRP3 activation, but not AIM2 or NLRC4 inflammasomes . Conversely, NLRP3 activation was increased in itaconate-depleted Irg1−/− macrophages . In addition, 4-OI inhibited NLRP3-dependent IL-1β release from PBMCs isolated from cryopyrin-associated periodic syndrome patients, and reduced inflammation in an in vivo model of urate-induced peritonitis . These results suggest a negative role of itaconate on inflammation.
| Metabolic brake model|| |
For easier explanation, here we postulate a simplified model, in which itaconate-ATF3 and itaconate-NRF2 axis are critical metabolic brakes on maintaining metabolic homeostasis to achieve anti-inflammation and tissue repair [Figure 2]. When cells are under inflammation, metabolic overload, itaconate levels are increased [Figure 1], by which metabolic brakes-induced physiological metabolic brake responses exert ameliorative roles to reduce metabolic stress (e.g., inflammation, metabolic diseases, tissue damages)-elicited adverse effects. Thus, without ATF3, other molecular brake become more rapidly wore down by stresses [Figure 2].
|Figure 2: The metabolic brake model. Itaconate-mediated regulations (e.g. itaconate-ATF3, itaconate-NRF2 axes) serve as potential “metabolic brakes” to conduct anti-inflammation, anti-oxidant and tissue repair effects. The “metabolic brake” exerts ameliorative roles on metabolic stresses (e.g. oxidative stress, excessive inflammation, metabolic overload, obesity) induced adverse effects. The image of wheel displayed in the center of the figure is originally downloaded (March 19, 2021) from the clipart-library.com, a free cliparts collection. NRF2: Nuclear factor erythroid 2-related factor 2, ARF3: AMP-dependent transcription factor 3|
Click here to view
| Conclusions|| |
Because NRF2 and its principal negative regulator KEAP1 are critical in the maintenance of redox, metabolic, and inflammation, the activators and inhibitors of NRF2 have been considered as therapeutic agents in chronic diseases,,. Similarly, cardiac ATF3 exerts a protective role on the amelioration of high fat diet-induced cardiac remodeling processes . Overexpression of ATF3 induced the trans-differentiation of white adipocytes into beige/brown adipocytes in vitro . Chemical ATF3 inducer sulfuretin counteracts weight gain and improves glucose tolerance in an ATF3 dependent manner, indicating that ATF3 induction can be a molecular target for preventing obesity and metabolic diseases . It is also shown that ST32da, a chemically synthesized ATF3 inducer, enhances ATF3 expression to inhibit lipogenesis and promote adipocyte browning by inhibiting the carbohydrate-responsive element-binding protein–stearoyl-CoA desaturase-1 axis . Accordingly, ATF3 is considered a therapeutic target for obesity and metabolic diseases,,,. Evidence described collectively suggest that itaconate derivatives may be used as therapeutic agents and the pathway-associated factors ATF3 and NRF2 may be served as therapeutic targets on the management of metabolic stress-associated diseases. New discoveries in this field may help the development of more effective therapeutic approach to manage stress-induced inflammation, tissue damages, and metabolic disorders.
Financial support and sponsorship
This work is supported by research funding from Ministry of Science and Technology, Taiwan (101-2320-B-320- 004-MY3, 105-2923-B-320-001-MY3, and 107-2311-B-320- 002-MY3), Tzu Chi University (TCIRP95002; TCIRP98001; and TCIRP101001) and Buddhist Tzu Chi Medical Foundation (TC-NHRI105-02; TCMMP104-06; TCMMP108-04; and TCAS-108-01).
Conflicts of interest
Prof. Hsin-Hou Chang, an editorial board member at Tzu Chi Medical Journal, had no role in the peer review process of or decision to publish this article. The other author declared no conflicts of interest in writing this paper..
| References|| |
Martínez-Reyes I, Chandel NS. Mitochondrial TCA cycle metabolites control physiology and disease. Nat Commun 2020;11:102.
Nelson MC, O'Connell RM. MicroRNAs: At the Interface of Metabolic Pathways and Inflammatory Responses by Macrophages. Front Immunol 2020;11:1797.
Mills E, O'Neill LA. Succinate: A metabolic signal in inflammation. Trends Cell Biol 2014;24:313-20.
Li R, Zhang P, Wang Y, Tao K. Itaconate: A metabolite regulates inflammation response and oxidative stress. Oxid Med Cell Longev 2020;2020:5404780.
Hooftman A, Angiari S, Hester S, Corcoran SE, Runtsch MC, Ling C, et al. The immunomodulatory metabolite itaconate modifies NLRP3 and inhibits inflammasome activation. Cell Metab 2020;32:468-78.e7.
Yang C, Liu T, Shi GP. Therapeutic potential of tricarboxylic acid cycle metabolite itaconate in cardiovascular diseases. EBioMedicine 2020;59:102938.
McBride MA, Owen AM, Stothers CL, Hernandez A, Luan L, Burelbach KR, et al. The metabolic basis of immune dysfunction following sepsis and trauma. Front Immunol 2020;11:1043.
Viola A, Munari F, Sánchez-Rodríguez R, Scolaro T, Castegna A. The metabolic signature of macrophage responses. Front Immunol 2019;10:1462.
O'Neill LA, Artyomov MN. Itaconate: The poster child of metabolic reprogramming in macrophage function. Nat Rev Immunol 2019;19:273-81.
Lampropoulou V, Sergushichev A, Bambouskova M, Nair S, Vincent EE, Loginicheva E, et al. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab 2016;24:158-66.
Nair S, Huynh JP, Lampropoulou V, Loginicheva E, Esaulova E, Gounder AP, et al. Irg1
expression in myeloid cells prevents immunopathology during M. tuberculosis infection. J Exp Med 2018;215:1035-45.
Liao ST, Han C, Xu DQ, Fu XW, Wang JS, Kong LY. 4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects. Nat Commun 2019;10:5091.
Swain A, Bambouskova M, Kim H, Andhey PS, Duncan D, Auclair K, et al. Comparative evaluation of itaconate and its derivatives reveals divergent inflammasome and type I interferon regulation in macrophages. Nat Metab 2020;2:594-602.
Cordes T, Wallace M, Michelucci A, Divakaruni AS, Sapcariu SC, Sousa C, et al. Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels. J Biol Chem 2016;291:14274-84.
Mills EL, Ryan DG, Prag HA, Dikovskaya D, Menon D, Zaslona Z, et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 2018;556:113-7.
Tang C, Wang X, Xie Y, Cai X, Yu N, Hu Y, et al. 4-Octyl itaconate activates Nrf2 signaling to inhibit pro-inflammatory cytokine production in peripheral blood mononuclear cells of systemic lupus erythematosus patients. Cell Physiol Biochem 2018;51:979-90.
Olagnier D, Brandtoft AM, Gunderstofte C, Villadsen NL, Krapp C, Thielke AL, et al. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nat Commun 2018;9:3506.
Ku HC, Cheng CF. Master regulator activating transcription factor 3 (ATF3) in metabolic homeostasis and cancer. Front Endocrinol (Lausanne) 2020;11:556.
Hai T, Wolfgang CD, Marsee DK, Allen AE, Sivaprasad U. ATF3 and stress responses. Gene Expr 1999;7:321-35.
Cui H, Li X, Han C, Wang QE, Wang H, Ding HF, et al. The stress-responsive gene ATF3 mediates dichotomous UV responses by regulating the Tip60 and p53 proteins. J Biol Chem 2016;291:10847-57.
Zmuda EJ, Qi L, Zhu MX, Mirmira RG, Montminy MR, Hai T. The roles of ATF3, an adaptive-response gene, in high-fat-diet-induced diabetes and pancreatic beta-cell dysfunction. Mol Endocrinol 2010;24:1423-33.
Boespflug ND, Kumar S, McAlees JW, Phelan JD, Grimes HL, Hoebe K, et al. ATF3 is a novel regulator of mouse neutrophil migration. Blood 2014;123:2084-93.
Demidova AR, Aau MY, Zhuang L, Yu Q. Dual regulation of Cdc25A by Chk1 and p53-ATF3 in DNA replication checkpoint control. J Biol Chem 2009;284:4132-9.
Turchi L, Fareh M, Aberdam E, Kitajima S, Simpson F, Wicking C, et al. ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress. Cell Death Differ 2009;16:728-37.
Sato A, Nakama K, Watanabe H, Satake A, Yamamoto A, Omi T, et al. Role of activating transcription factor 3 protein ATF3 in necrosis and apoptosis induced by 5-fluoro-2'-deoxyuridine. FEBS J 2014;281:1892-900.
Fang J, Ji YX, Zhang P, Cheng L, Chen Y, Chen J, et al. Hepatic IRF2BP2 mitigates nonalcoholic fatty liver disease by directly repressing the transcription of ATF3. Hepatology 2020;71:1592-608.
Glal D, Sudhakar JN, Lu HH, Liu MC, Chiang HY, Liu YC, et al. ATF3 Sustains IL-22-Induced STAT3 phosphorylation to maintain mucosal immunity through inhibiting phosphatases. Front Immunol 2018;9:2522.
Allison MB, Pan W, MacKenzie A, Patterson C, Shah K, Barnes T, et al. Defining the transcriptional targets of leptin reveals a role for Atf3
in leptin action. Diabetes 2018;67:1093-104.
Wang J, Cheng W, Wang Z, Xin L, Zhang W. ATF3 inhibits the inflammation induced by Mycoplasma pneumonia in vitro
and in vivo
. Pediatr Pulmonol 2017;52:1163-70.
Zhao Q, Yang X, Cai D, Ye L, Hou Y, Zhang L, et al. Echinacoside protects against MPP(+)-induced neuronal apoptosis via ROS/ATF3/CHOP pathway regulation. Neurosci Bull 2016;32:349-62.
Nie D, Chen Z, Ebrahimi-Fakhari D, Di Nardo A, Julich K, Robson VK, et al. The stress-induced Atf3-gelsolin cascade underlies dendritic spine deficits in neuronal models of tuberous sclerosis complex. J Neurosci 2015;35:10762-72.
Chen HH, Lai PF, Lan YF, Cheng CF, Zhong WB, Lin YF, et al. Exosomal ATF3 RNA attenuates pro-inflammatory gene MCP-1 transcription in renal ischemia-reperfusion. J Cell Physiol 2014;229:1202-11.
Lai PF, Cheng CF, Lin H, Tseng TL, Chen HH, Chen SH. ATF3 protects against LPS-induced inflammation in mice via inhibiting HMGB1 expression. Evid Based Complement Alternat Med 2013;2013:716481.
Lan YF, Chen HH, Lai PF, Cheng CF, Huang YT, Lee YC, et al. MicroRNA-494 reduces ATF3 expression and promotes AKI. J Am Soc Nephrol 2012;23:2012-23.
Cheng CF, Lin H. Acute kidney injury and the potential for ATF3-regulated epigenetic therapy. Toxicol Mech Methods 2011;21:362-6.
Wu S, Hsu LA, Cheng CF, Teng MS, Chou HH, Lin H, et al. Effect of obesity on the association between ATF3 gene haplotypes and C-reactive protein level in Taiwanese. Clin Chim Acta 2011;412:1026-31.
Li HF, Cheng CF, Liao WJ, Lin H, Yang RB. ATF3-mediated epigenetic regulation protects against acute kidney injury. J Am Soc Nephrol 2010;21:1003-13.
Whitmore MM, Iparraguirre A, Kubelka L, Weninger W, Hai T, Williams BR. Negative regulation of TLR-signaling pathways by activating transcription factor-3. J Immunol 2007;179:3622-30.
Khuu CH, Barrozo RM, Hai T, Weinstein SL. Activating transcription factor 3 (ATF3) represses the expression of CCL4 in murine macrophages. Mol Immunol 2007;44:1598-605.
Gilchrist M, Thorsson V, Li B, Rust AG, Korb M, Roach JC, et al. Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4. Nature 2006;441:173-8.
Bambouskova M, Gorvel L, Lampropoulou V, Sergushichev A, Loginicheva E, Johnson K, et al. Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis. Nature 2018;556:501-4.
Nyunt T, Britton M, Wanichthanarak K, Budamagunta M, Voss JC, Wilson DW, et al. Mitochondrial oxidative stress-induced transcript variants of ATF3 mediate lipotoxic brain microvascular injury. Free Radic Biol Med 2019;143:25-46.
Jang MK, Son Y, Jung MH. ATF3 plays a role in adipocyte hypoxia-mediated mitochondria dysfunction in obesity. Biochem Biophys Res Commun 2013;431:421-7.
Lv D, Meng D, Zou FF, Fan L, Zhang P, Yu Y, et al. Activating transcription factor 3 regulates survivability and migration of vascular smooth muscle cells. IUBMB Life 2011;63:62-9.
Bueno M, Brands J, Voltz L, Fiedler K, Mays B, St Croix C, et al. ATF3 represses PINK1 gene transcription in lung epithelial cells to control mitochondrial homeostasis. Aging Cell 2018;17:e12720.
Ahmed SM, Luo L, Namani A, Wang XJ, Tang X. Nrf2 signaling pathway: Pivotal roles in inflammation. Biochim Biophys Acta Mol Basis Dis 2017;1863:585-97.
Kobayashi EH, Suzuki T, Funayama R, Nagashima T, Hayashi M, Sekine H, et al. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun 2016;7:11624.
Wu MS, Sun DS, Lin YC, Cheng CL, Hung SC, Chen PK, et al. Nanodiamonds protect skin from ultraviolet B-induced damage in mice. J Nanobiotechnology 2015;13:35.
Tsai CL, Sun DS, Su MT, Lien TS, Chen YH, Lin CY, et al. Suppressed humoral immunity is associated with dengue nonstructural protein NS1-elicited anti-death receptor antibody fractions in mice. Sci Rep 2020;10:6294.
Sun DS, Ho PH, Chang HH. Soluble P-selectin rescues viper venom-induced mortality through anti-inflammatory properties and PSGL-1 pathway-mediated correction of hemostasis. Sci Rep 2016;6:35868.
Sun DS, Chang YW, Kau JH, Huang HH, Ho PH, Tzeng YJ, et al. Soluble P-selectin rescues mice from anthrax lethal toxin-induced mortality through PSGL-1 pathway-mediated correction of hemostasis. Virulence 2017;8:1216-28.
Sun DS, Chang YC, Lien TS, King CC, Shih YL, Huang HS, et al. Endothelial cell sensitization by death receptor fractions of an anti-dengue nonstructural protein 1 antibody induced plasma leakage, coagulopathy, and mortality in mice. J Immunol 2015;195:2743-53.
Lin YY, Hu CT, Sun DS, Lien TS, Chang HH. Thioacetamide-induced liver damage and thrombocytopenia is associated with induction of antiplatelet autoantibody in mice. Sci Rep 2019;9:17497.
Hsueh PT, Lin HH, Wang HH, Liu CL, Ni WF, Liu JK, et al. Immune imbalance of global gene expression, and cytokine, chemokine and selectin levels in the brains of offspring with social deficits via maternal immune activation. Genes Brain Behav 2018;17:e12479.
Ho YY, Sun DS, Chang HH. Silver nanoparticles protect skin from ultraviolet b-induced damage in mice. Int J Mol Sci 2020;21:7082.
Chen TL, Chiang YW, Lin GL, Chang HH, Lien TS, Sheh MH, et al. Different effects of granulocyte colony-stimulating factor and erythropoietin on erythropoiesis. Stem Cell Res Ther 2018;9:119.
Chan H, Huang HS, Sun DS, Lee CJ, Lien TS, Chang HH. TRPM8 and RAAS-mediated hypertension is critical for cold-induced immunosuppression in mice. Oncotarget 2018;9:12781-95.
Lien TS, Hao C, Sun DS, Wu JC, Lin YY, Lin GL, et al. Exposure of platelets to dengue vrus and envelope protein domain III induces Nlrp3 inflammasome-dependent platelet cell death and thrombocytopenia in mice. Front Immunol 2021;12:616394.
Chang YS, Ko BH, Ju JC, Chang HH, Huang SH, Lin CW. SARS unique domain (SUD) of severe acute rspiratory sSyndrome coronavirus induces NLRP3 inflammasome-dependent CXCL10-mediated pulmonary inflammation. Int J Mol Sci 2020;21:3179.
Lien TS, Sun DS, Wu CY, Chang HH. Exposure to dengue envelope protein domain III induces nlrp3 inflammasome-dependent endothelial dysfunction and hemorrhage in mice. Front Immunol 2021;12:617251.
Lien TS, Sun DS, Chang CM, Wu CY, Dai MS, Chan H, et al. Dengue virus and antiplatelet autoantibodies synergistically induce haemorrhage through Nlrp3-inflammasome and FcγRIII. Thromb Haemost 2015;113:1060-70.
Zahid A, Li B, Kombe AJK, Jin T, Tao J. Pharmacological inhibitors of the NLRP3 inflammasome. Front Immunol 2019;10:2538.
Lage SL, Dominical VM, Wong CS, Sereti I. Evaluation of canonical inflammasome activation in human monocytes by imaging flow cytometry. Front Immunol 2019;10:1284.
Li LH, Lin JS, Chiu HW, Lin WY, Ju TC, Chen FH, et al. Mechanistic insight into the activation of the NLRP3 Inflammasome by Neisseria gonorrhoeae
in Macrophages. Front Immunol 2019;10:1815.
Zhao C, Zhao W. NLRP3 inflammasome-A key player in antiviral responses. Front Immunol 2020;11:211.
de Rivero Vaccari JC, Dietrich WD, Keane RW, de Rivero Vaccari JP. The Inflammasome in Times of COVID-19. Front Immunol 2020;11:583373.
Fusco R, Siracusa R, Genovese T, Cuzzocrea S, Di Paola R. Focus on the role of NLRP3 inflammasome in diseases. Int J Mol Sci 2020;21:4223.
Yuk JM, Silwal P, Jo EK. Inflammasome and mitophagy connection in health and disease. Int J Mol Sci 2020;21:4714.
Irrera N, Russo M, Pallio G, Bitto A, Mannino F, Minutoli L, et al. The role of NLRP3 inflammasome in the pathogenesis of traumatic brain injury. Int J Mol Sci 2020;21:6204.
Lien TS, Sun DS, Hung SC, Wu WS, Chang HH. Dengue virus envelope protein domain III induces Nlrp3 inflammasome-dependent NETosis-mediated inflammation in mice. Front Immunol 2021;12:618577.
Harber KJ, de Goede KE, Verberk SG, Meinster E, de Vries HE, van Weeghel M, et al. Succinate is an inflammation-induced immunoregulatory metabolite in macrophages. Metabolites 2020;10:372.
Cuadrado A, Rojo AI, Wells G, Hayes JD, Cousin SP, Rumsey WL, et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov 2019;18:295-317.
Cores Á, Piquero M, Villacampa M, León R, Menéndez JC. NRF2 regulation processes as a source of potential drug targets against neurodegenerative diseases. Biomolecules 2020;10:904.
Robledinos-Antón N, Fernández-Ginés R, Manda G, Cuadrado A. Activators and inhibitors of NRF2: A review of their potential for clinical development. Oxid Med Cell Longev 2019;2019:9372182.
Kalfon R, Koren L, Aviram S, Schwartz O, Hai T, Aronheim A. ATF3 expression in cardiomyocytes preserves homeostasis in the heart and controls peripheral glucose tolerance. Cardiovasc Res 2017;113:134-46.
Cheng CF, Ku HC, Cheng JJ, Chao SW, Li HF, Lai PF, et al. Adipocyte browning and resistance to obesity in mice is induced by expression of ATF3. Commun Biol 2019;2:389.
Kim S, Song NJ, Bahn G, Chang SH, Yun UJ, Ku JM, et al. Atf3 induction is a therapeutic target for obesity and metabolic diseases. Biochem Biophys Res Commun 2018;504:903-8.
[Figure 1], [Figure 2]