The multifaceted roles of activating transcription factor 3 (ATF3) in inflammatory responses – Potential target to regulate neuroinflammation in acute brain injury

Activating transcription factor 3 (ATF3) is one of the most important transcription factors that respond to and exert dual effects on inflammatory responses. Recently, the involvement of ATF3 in the neuroinflammatory response to acute brain injury (ABI) has been highlighted. It functions by regulating neuroimmune activation and the production of neuroinflammatory mediators. Notably, recent clinical evidence suggests that ATF3 may serve as a potential ideal biomarker of the long-term prognosis of ABI patients. This mini-review describes the essential inflammation modulatory roles of ATF3 in different disease contexts and summarizes the regulatory mechanisms of ATF3 in the ABI-induced neuroinflammation.

[1]  Xi Yang,et al.  ATF3 in atherosclerosis: a controversial transcription factor , 2022, Journal of Molecular Medicine.

[2]  Hui-Chun Huang,et al.  Predictive value of longitudinal changes of serum matrix metalloproteinase-9 and brain-derived neurotrophic factor in acute ischemic stroke , 2022, Frontiers in Aging Neuroscience.

[3]  Lianwen Zhang,et al.  Glucose Starvation Causes ptauS409 Increase in N2a Cells Through ATF3/PKAcα Signaling Pathway , 2022, Neurochemical Research.

[4]  S. Lalwani,et al.  Altered expression of activating transcription factor 3 in the hippocampus of patients with mesial temporal lobe epilepsy-hippocampal sclerosis (MTLE-HS) , 2022, The International journal of neuroscience.

[5]  Jianyun Yan,et al.  A novel function of ATF3 in suppression of ferroptosis in mouse heart suffered ischemia/reperfusion. , 2022, Free radical biology & medicine.

[6]  T. G. Singh,et al.  Intervention of neuroinflammation in the traumatic brain injury trajectory: In vivo and clinical approaches. , 2022, International immunopharmacology.

[7]  Yangfan Wang,et al.  Phagocytic microglia and macrophages in brain injury and repair , 2022, CNS neuroscience & therapeutics.

[8]  Hao Wang,et al.  Transplantation of Roxadustat‐preconditioned bone marrow stromal cells improves neurological function recovery through enhancing grafted cell survival in ischemic stroke rats , 2022, CNS neuroscience & therapeutics.

[9]  A. Dzutsev,et al.  Microbiota and adipocyte mitochondrial damage in type 2 diabetes are linked by Mmp12+ macrophages , 2022, The Journal of experimental medicine.

[10]  Xiuli Yi,et al.  Nanoparticle delivery of miR-21-3p sensitizes melanoma to anti-PD-1 immunotherapy by promoting ferroptosis , 2022, Journal for ImmunoTherapy of Cancer.

[11]  Jeonghyun Choi,et al.  Pre‐ and post‐conditioning with poly I:C exerts neuroprotective effect against cerebral ischemia injury in animal models: A systematic review and meta‐analysis , 2022, CNS neuroscience & therapeutics.

[12]  J. Björkegren,et al.  Atherosclerosis: Recent developments , 2022, Cell.

[13]  Chan Chen,et al.  Transcriptome Profiles of IncRNA and mRNA Highlight the Role of Ferroptosis in Chronic Neuropathic Pain With Memory Impairment , 2022, Frontiers in Cell and Developmental Biology.

[14]  Shixin Xu,et al.  Microglia: The Hub of Intercellular Communication in Ischemic Stroke , 2022, Frontiers in Cellular Neuroscience.

[15]  Jinfang Liu,et al.  TFCP2, a binding protein of ATF3, promotes the progression of glioma by activating the synthesis of serine. , 2022, Experimental cell research.

[16]  Xuehai Wu,et al.  Neuroinflammation Following Traumatic Brain Injury: Take It Seriously or Not , 2022, Frontiers in Immunology.

[17]  Dakang Xu,et al.  ATF3 Positively Regulates Antibacterial Immunity by Modulating Macrophage Killing and Migration Functions , 2022, Frontiers in Immunology.

[18]  Xiuxin Fu,et al.  Protective role of activating transcription factor 3 against neuronal damage in rats with cerebral ischemia , 2022, Brain and behavior.

[19]  P. Adlard,et al.  Deferiprone attenuates neuropathology and improves outcome following traumatic brain injury , 2022, British journal of pharmacology.

[20]  N. Na,et al.  Identification of Subtypes and a Delayed Graft Function Predictive Signature Based on Ferroptosis in Renal Ischemia-Reperfusion Injury , 2022, Frontiers in Cell and Developmental Biology.

[21]  A. Pandit,et al.  Role and therapeutic implications of protein glycosylation in neuroinflammation. , 2022, Trends in molecular medicine.

[22]  D. Geschwind,et al.  Core transcription programs controlling injury-induced neurodegeneration of retinal ganglion cells , 2022, Neuron.

[23]  E. Krüger,et al.  Proteasome dysfunction disrupts adipogenesis and induces inflammation via ATF3 , 2022, bioRxiv.

[24]  Yang Liu,et al.  Neuroinflammation in perioperative neurocognitive disorders: From bench to the bedside , 2022, CNS neuroscience & therapeutics.

[25]  Cheng Li,et al.  BMPER alleviates ischemic brain injury by protecting neurons and inhibiting neuroinflammation via Smad3‐Akt‐Nrf2 pathway , 2021, CNS neuroscience & therapeutics.

[26]  Jun Liu,et al.  Identification and Validation of ATF3 Serving as a Potential Biomarker and Correlating With Pharmacotherapy Response and Immune Infiltration Characteristics in Rheumatoid Arthritis , 2021, Frontiers in Molecular Biosciences.

[27]  Yuwei Zhou,et al.  Substrate Viscoelasticity Amplifies Distinctions between Transient and Persistent LPS‐Induced Signals , 2021, Advanced healthcare materials.

[28]  R. Turner,et al.  Neuroinflammation as a Key Driver of Secondary Neurodegeneration Following Stroke? , 2021, International journal of molecular sciences.

[29]  Yawei Liu,et al.  Transcriptomic Analysis Reveals that Activating Transcription Factor 3/c-Jun/Lgals3 Axis Is Associated with Central Diabetes Insipidus after Hypothalamic Injury , 2021, Neuroendocrinology.

[30]  V. Risbrough,et al.  Role of Inflammation in Traumatic Brain Injury–Associated Risk for Neuropsychiatric Disorders: State of the Evidence and Where Do We Go From Here , 2021, Biological Psychiatry.

[31]  K. Lu,et al.  Induction of IL-6Rα by ATF3 enhances IL-6 mediated sorafenib and regorafenib resistance in hepatocellular carcinoma. , 2021, Cancer letters.

[32]  D. McGavern,et al.  Antimicrobial immunity impedes CNS vascular repair following brain injury , 2021, Nature Immunology.

[33]  C. Adams,et al.  Exercise-induced angiogenesis is dependent on metabolically primed ATF3/4+ endothelial cells , 2021, Cell metabolism.

[34]  S. Guglietta,et al.  Chronic complement dysregulation drives neuroinflammation after traumatic brain injury: a transcriptomic study , 2021, Acta Neuropathologica Communications.

[35]  X. Ji,et al.  Neuroprotective effects and mechanisms of ischemic/hypoxic preconditioning on neurological diseases , 2021, CNS neuroscience & therapeutics.

[36]  Wenling Zhang,et al.  Emerging roles of activating transcription factor (ATF) family members in tumourigenesis and immunity: Implications in cancer immunotherapy , 2021, Genes & diseases.

[37]  C. Keene,et al.  Traumatic Brain Injury and Risk of Neurodegenerative Disorder , 2021, Biological Psychiatry.

[38]  Alyssa R. Richman,et al.  p38 MAP Kinase Signaling in Microglia Plays a Sex-Specific Protective Role in CNS Autoimmunity and Regulates Microglial Transcriptional States , 2021, Frontiers in Immunology.

[39]  T. Eleftheriadis,et al.  Role of indoleamine 2,3-dioxygenase in ischemia-reperfusion injury of renal tubular epithelial cells , 2021, Molecular medicine reports.

[40]  Xu Zhang,et al.  Single-cell transcriptomic analysis of somatosensory neurons uncovers temporal development of neuropathic pain , 2021, Cell Research.

[41]  R. Leak,et al.  Microglial/Macrophage polarization and function in brain injury and repair after stroke , 2021, CNS neuroscience & therapeutics.

[42]  J. C. Love,et al.  Longitudinal transcriptomics define the stages of myeloid activation in the living human brain after intracerebral hemorrhage , 2021, Science Immunology.

[43]  Jian Zhou,et al.  ATF3: a novel biomarker for the diagnosis of acute kidney injury after cardiac surgery , 2021, Annals of translational medicine.

[44]  N. Tyagi,et al.  Effects of fibrinogen synthesis inhibition on vascular cognitive impairment during traumatic brain injury in mice , 2020, Brain Research.

[45]  D. Vivien,et al.  Filling the gaps on stroke research: Focus on inflammation and immunity , 2020, Brain, Behavior, and Immunity.

[46]  D. Belsham,et al.  Bisphenol A Induces Agrp Gene Expression in Hypothalamic Neurons through a Mechanism Involving ATF3 , 2020, Neuroendocrinology.

[47]  M. Wintermark,et al.  Supracardiac atherosclerosis in embolic stroke of undetermined source: the underestimated source. , 2020, European heart journal.

[48]  Johan Bo Davidsson,et al.  Diffuse Axonal Injury in the Rat Brain: Axonal Injury and Oligodendrocyte Activity Following Rotational Injury , 2020, Brain sciences.

[49]  M. Hung,et al.  ADORA1 Inhibition Promotes Tumor Immune Evasion by Regulating the ATF3-PD-L1 Axis. , 2020, Cancer cell.

[50]  D. Geschwind,et al.  Transcriptional Reprogramming of Distinct Peripheral Sensory Neuron Subtypes after Axonal Injury , 2019, Neuron.

[51]  J. Rutledge,et al.  Mitochondrial oxidative stress-induced transcript variants of ATF3 mediate lipotoxic brain microvascular injury. , 2019, Free radical biology & medicine.

[52]  G. Stoll,et al.  Thrombo-inflammation in acute ischaemic stroke — implications for treatment , 2019, Nature Reviews Neurology.

[53]  N. Selvamurugan,et al.  Role of activating transcription factor 3 and its interacting proteins under physiological and pathological conditions. , 2018, International journal of biological macromolecules.

[54]  Jian-ru Li,et al.  Fluoxetine attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage: a possible role for the regulation of TLR4/MyD88/NF-κB signaling pathway , 2018, Journal of Neuroinflammation.

[55]  Xin Wang,et al.  The peripheral immune response after stroke—A double edge sword for blood‐brain barrier integrity , 2018, CNS neuroscience & therapeutics.

[56]  A. Ignatius,et al.  Neuroinflammation after Traumatic Brain Injury Is Enhanced in Activating Transcription Factor 3 Mutant Mice. , 2018, Journal of Neurotrauma.

[57]  Q. Tang,et al.  Activating transcription factor 3 in cardiovascular diseases: a potential therapeutic target , 2018, Basic Research in Cardiology.

[58]  J. Ryu,et al.  Fibrinogen in neurological diseases: mechanisms, imaging and therapeutics , 2018, Nature Reviews Neuroscience.

[59]  Maxim N. Artyomov,et al.  Electrophilic properties of itaconate and derivatives regulate the IκBζ–ATF3 inflammatory axis , 2018, Nature.

[60]  Yanqiao Zhang,et al.  Activating transcription factor 3 in immune response and metabolic regulation. , 2017, Liver research.

[61]  D. Menon,et al.  Monitoring the Neuroinflammatory Response Following Acute Brain Injury , 2017, Front. Neurol..

[62]  P. Reaven,et al.  HDL inhibits saturated fatty acid mediated augmentation of innate immune responses in endothelial cells by a novel pathway. , 2017, Atherosclerosis.

[63]  Hülya Bayır,et al.  The far-reaching scope of neuroinflammation after traumatic brain injury , 2017, Nature Reviews Neurology.

[64]  James J. McCarthy,et al.  Cortical Thickness in Mild Traumatic Brain Injury. , 2016, Journal of neurotrauma.

[65]  D. McGavern,et al.  Inflammatory neuroprotection following traumatic brain injury , 2016, Science.

[66]  E. Hinoi,et al.  Protective upregulation of activating transcription factor‐3 against glutamate neurotoxicity in neuronal cells under ischemia , 2016, Journal of neuroscience research.

[67]  P. Bergold Treatment of traumatic brain injury with anti-inflammatory drugs , 2016, Experimental Neurology.

[68]  Shruti V. Kabadi,et al.  Repeated Mild Traumatic Brain Injury Causes Chronic Neuroinflammation, Changes in Hippocampal Synaptic Plasticity, and Associated Cognitive Deficits , 2014, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[69]  H. Feng,et al.  Curcumin attenuates acute inflammatory injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway in experimental traumatic brain injury , 2014, Journal of Neuroinflammation.

[70]  Melissa D. Laird,et al.  High mobility group box protein‐1 promotes cerebral edema after traumatic brain injury via activation of toll‐like receptor 4 , 2014, Glia.

[71]  E. Latz,et al.  High density lipoprotein mediates anti-inflammatory transcriptional reprogramming of macrophages via the transcriptional repressor ATF3 , 2013, Nature Immunology.

[72]  B. Prakken,et al.  Cerebral ischemia initiates an immediate innate immune response in neonates during cardiac surgery , 2013, Journal of Neuroinflammation.

[73]  D. Loane,et al.  Neuroinflammation after traumatic brain injury: Opportunities for therapeutic intervention , 2012, Brain, Behavior, and Immunity.

[74]  L. Wang,et al.  Increased inflammation and brain injury after transient focal cerebral ischemia in activating transcription factor 3 knockout mice , 2012, Neuroscience.

[75]  R. Morita,et al.  Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain , 2012, Nature Medicine.

[76]  R. Moritz,et al.  ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol–induced lipid body formation , 2012, The Journal of experimental medicine.

[77]  Tsonwin Hai,et al.  ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression , 2011, Nature Medicine.

[78]  S. Jung,et al.  Role of activating transcription factor 3 in ischemic penumbra region following transient middle cerebral artery occlusion and reperfusion injury , 2011, Neuroscience Research.

[79]  D. Janigro,et al.  A Dynamic in vitro BBB Model for the Study of Immune Cell Trafficking into the Central Nervous System , 2011, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[80]  S. Akira,et al.  Toll-like receptor 4 (TLR4), but not TLR3 or TLR9, knock-out mice have neuroprotective effects against focal cerebral ischemia , 2010, Neuroscience.

[81]  Guohong Li,et al.  Inflammatory mechanisms in ischemic stroke: role of inflammatory cells , 2010, Journal of leukocyte biology.

[82]  David L. Thomas,et al.  Overexpression of Heat Shock Protein 27 Reduces Cortical Damage after Cerebral Ischemia , 2010, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[83]  Matthew R. Thompson,et al.  ATF3 transcription factor and its emerging roles in immunity and cancer , 2009, Journal of Molecular Medicine.

[84]  Tsonwin Hai,et al.  Activating transcription factor 3 (ATF3) represses the expression of CCL4 in murine macrophages. , 2007, Molecular immunology.

[85]  Kathleen A. Kennedy,et al.  Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4 , 2006, Nature.

[86]  J. Younger,et al.  The Role of Complement C3 in Intracerebral Hemorrhage-Induced Brain Injury , 2006, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[87]  B. Stoica,et al.  Gene expression profile changes are commonly modulated across models and species after traumatic brain injury. , 2003, Journal of neurotrauma.

[88]  M. Isobe,et al.  ATF3 inhibits doxorubicin-induced apoptosis in cardiac myocytes: a novel cardioprotective role of ATF3. , 2002, Journal of molecular and cellular cardiology.

[89]  OUP accepted manuscript , 2022, European Heart Journal.

[90]  R. Leak,et al.  Microglial and macrophage polarization—new prospects for brain repair , 2015, Nature Reviews Neurology.