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He W, Mu X, Wu X, Liu Y, Deng J, Liu Y, Han F, Nie X. The cGAS-STING pathway: a therapeutic target in diabetes and its complications. BURNS & TRAUMA 2024; 12:tkad050. [PMID: 38312740 PMCID: PMC10838060 DOI: 10.1093/burnst/tkad050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 08/22/2023] [Accepted: 10/09/2023] [Indexed: 02/06/2024]
Abstract
Diabetic wound healing (DWH) represents a major complication of diabetes where inflammation is a key impediment to proper healing. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has emerged as a central mediator of inflammatory responses to cell stress and damage. However, the contribution of cGAS-STING activation to impaired healing in DWH remains understudied. In this review, we examine the evidence that cGAS-STING-driven inflammation is a critical factor underlying defective DWH. We summarize studies revealing upregulation of the cGAS-STING pathway in diabetic wounds and discuss how this exacerbates inflammation and senescence and disrupts cellular metabolism to block healing. Partial pharmaceutical inhibition of cGAS-STING has shown promise in damping inflammation and improving DWH in preclinical models. We highlight key knowledge gaps regarding cGAS-STING in DWH, including its relationships with endoplasmic reticulum stress and metal-ion signaling. Elucidating these mechanisms may unveil new therapeutic targets within the cGAS-STING pathway to improve healing outcomes in DWH. This review synthesizes current understanding of how cGAS-STING activation contributes to DWH pathology and proposes future research directions to exploit modulation of this pathway for therapeutic benefit.
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Affiliation(s)
- Wenjie He
- Key Lab of the Basic Pharmacology of the Ministry of Education, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
- College of Pharmacy, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
| | - Xingrui Mu
- Key Lab of the Basic Pharmacology of the Ministry of Education, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
- College of Pharmacy, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
| | - Xingqian Wu
- Key Lab of the Basic Pharmacology of the Ministry of Education, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
- College of Pharmacy, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
| | - Ye Liu
- Key Lab of the Basic Pharmacology of the Ministry of Education, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
- College of Pharmacy, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
| | - Junyu Deng
- Key Lab of the Basic Pharmacology of the Ministry of Education, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
- College of Pharmacy, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
| | - Yiqiu Liu
- Key Lab of the Basic Pharmacology of the Ministry of Education, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
- College of Pharmacy, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
| | - Felicity Han
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Xuqiang Nie
- Key Lab of the Basic Pharmacology of the Ministry of Education, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
- College of Pharmacy, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
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2
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Liu Y, Pu F. Updated roles of cGAS-STING signaling in autoimmune diseases. Front Immunol 2023; 14:1254915. [PMID: 37781360 PMCID: PMC10538533 DOI: 10.3389/fimmu.2023.1254915] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 08/29/2023] [Indexed: 10/03/2023] Open
Abstract
Natural immunity, the first line for the body to defense against the invasion of pathogen, serves as the body's perception of the presence of pathogens depends on nucleic acid recognition mechanisms. The cyclic GMP-AMP synthase-stimulator of the interferon gene (cGAS-STING) signaling pathway is considered an essential pattern recognition and effector pathway in the natural immune system and is mainly responsible for recognizing DNA molecules present in the cytoplasm and activating downstream signaling pathways to generate type I interferons and some other inflammatory factors. STING, a crucial junction protein in the innate immune system, exerts an essential role in host resistance to external pathogen invasion. Also, STING, with the same character of inflammatory molecules, is inseparable from the body's inflammatory response. In particular, when the expression of STING is upregulated or its related signaling pathways are overactivated, the body may develop serious infectious disorders due to the generation of excessive inflammatory responses, non-infectious diseases, and autoimmune diseases. In recent years, accumulating studies indicated that the abnormal activation of the natural immune cGAS-STING signaling pathway modulated by the nucleic acid receptor cGAS closely associated with the development and occurrence of autoimmune diseases (AID). Thereof, to explore an in-depth role of STING and its related signaling pathways in the diseases associated with inflammation may be helpful to provide new avenues for the treatment of these diseases in the clinic. This article reviews the activation process of the cGAS-STING signaling pathways and its related important roles, and therapeutic drugs in AID, aiming to improve our understanding of AID and achieve better diagnosis and treatment of AID.
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Affiliation(s)
- Ya Liu
- Department of Rheumatology and Immunology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Skin Infection and Immunity, Wuhan No.1 Hospital, Wuhan, Hubei, China
| | - Feifei Pu
- Hubei Key Laboratory of Skin Infection and Immunity, Wuhan No.1 Hospital, Wuhan, Hubei, China
- Department of Orthopedics, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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3
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Li Y, Li X, Yi J, Cao Y, Qin Z, Zhong Z, Yang W. Nanoparticle-Mediated STING Activation for Cancer Immunotherapy. Adv Healthc Mater 2023:e2300260. [PMID: 36905358 DOI: 10.1002/adhm.202300260] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 03/02/2023] [Indexed: 03/12/2023]
Abstract
As the first line of host defense against pathogenic infections, innate immunity plays a key role in antitumor immunotherapy. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) (cGAS-STING) pathway has attracted much attention because of the secretion of various proinflammatory cytokines and chemokines. Many STING agonists have been identified and applied into preclinical or clinical trials for cancer immunotherapy. However, the fast excretion, low bioavailability, nonspecificity, and adverse effects of the small molecule STING agonists limit their therapeutic efficacy and in vivo application. Nanodelivery systems with appropriate size, charge, and surface modification are capable of addressing these dilemmas. In this review, the mechanism of the cGAS-STING pathway is discussed and the STING agonists, focusing on nanoparticle-mediated STING therapy and combined therapy for cancers, are summarized. Finally, the future direction and challenges of nano-STING therapy are expounded, emphasizing the pivotal scientific problems and technical bottlenecks and hoping to provide general guidance for its clinical application.
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Affiliation(s)
- Yongjuan Li
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, 450001, China.,The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China
| | - Xinyan Li
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, 450001, China.,The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China
| | - Jinmeng Yi
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, 450001, China.,The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China
| | - Yongjian Cao
- School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou University, Zhengzhou, Henan, 450001, China
| | - Zhihai Qin
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, 450001, China.,The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China
| | - Zhiyuan Zhong
- Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, State Key Laboratory of Radiation Medicine and Protection, and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Weijing Yang
- School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou University, Zhengzhou, Henan, 450001, China
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MacLauchlan S, Fitzgerald KA, Gravallese EM. Intracellular Sensing of DNA in Autoinflammation and Autoimmunity. Arthritis Rheumatol 2022; 74:1615-1624. [PMID: 35656967 PMCID: PMC9529773 DOI: 10.1002/art.42256] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 03/25/2022] [Accepted: 05/27/2022] [Indexed: 11/10/2022]
Abstract
Evidence has shown that DNA is a pathogen-associated molecular pattern, posing a unique challenge in the discrimination between endogenous and foreign DNA. This challenge is highlighted by certain autoinflammatory diseases that arise from monogenic mutations and result in periodic flares of inflammation, typically in the absence of autoantibodies or antigen-specific T lymphocytes. Several autoinflammatory diseases arise due to mutations in genes that normally prevent the accrual of endogenous DNA or are due to mutations that cause activation of intracellular DNA-sensing pathway components. Evidence from genetically modified murine models further support an ability of endogenous DNA and DNA sensing to drive disease pathogenesis, prompting the question of whether endogenous DNA can also induce inflammation in human autoimmune diseases. In this review, we discuss the current understanding of intracellular DNA sensing and downstream signaling pathways as they pertain to autoinflammatory disease, including the development of monogenic disorders such as Stimulator of interferon genes-associated vasculopathy with onset in infancy and Aicardi-Goutières syndrome. In addition, we discuss systemic rheumatic diseases, including certain forms of systemic lupus erythematosus, familial chilblain lupus, and other diseases with established links to intracellular DNA-sensing pathways, and highlight the lessons learned from these examples as they apply to the development of therapies targeting these pathways.
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Affiliation(s)
- Susan MacLauchlan
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Katherine A. Fitzgerald
- Program in Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School
| | - Ellen M. Gravallese
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
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5
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The cGAS-STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy. Acta Pharm Sin B 2022; 12:50-75. [PMID: 35127372 PMCID: PMC8799861 DOI: 10.1016/j.apsb.2021.05.011] [Citation(s) in RCA: 162] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/05/2021] [Accepted: 04/15/2021] [Indexed: 12/12/2022] Open
Abstract
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling exert essential regulatory function in microbial-and onco-immunology through the induction of cytokines, primarily type I interferons. Recently, the aberrant and deranged signaling of the cGAS-STING axis is closely implicated in multiple sterile inflammatory diseases, including heart failure, myocardial infarction, cardiac hypertrophy, nonalcoholic fatty liver diseases, aortic aneurysm and dissection, obesity, etc. This is because of the massive loads of damage-associated molecular patterns (mitochondrial DNA, DNA in extracellular vesicles) liberated from recurrent injury to metabolic cellular organelles and tissues, which are sensed by the pathway. Also, the cGAS-STING pathway crosstalk with essential intracellular homeostasis processes like apoptosis, autophagy, and regulate cellular metabolism. Targeting derailed STING signaling has become necessary for chronic inflammatory diseases. Meanwhile, excessive type I interferons signaling impact on cardiovascular and metabolic health remain entirely elusive. In this review, we summarize the intimate connection between the cGAS-STING pathway and cardiovascular and metabolic disorders. We also discuss some potential small molecule inhibitors for the pathway. This review provides insight to stimulate interest in and support future research into understanding this signaling axis in cardiovascular and metabolic tissues and diseases.
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Key Words
- AA, amino acids
- AAD, aortic aneurysm and dissection
- AKT, protein kinase B
- AMPK, AMP-activated protein kinase
- ATP, adenosine triphosphate
- Ang II, angiotensin II
- CBD, C-binding domain
- CDG, c-di-GMP
- CDNs, cyclic dinucleotides
- CTD, C-terminal domain
- CTT, C-terminal tail
- CVDs, cardiovascular diseases
- Cardiovascular diseases
- Cys, cysteine
- DAMPs, danger-associated molecular patterns
- Damage-associated molecular patterns
- DsbA-L, disulfide-bond A oxidoreductase-like protein
- ER stress
- ER, endoplasmic reticulum
- GTP, guanosine triphosphate
- HAQ, R71H-G230A-R293Q
- HFD, high-fat diet
- ICAM-1, intracellular adhesion molecule 1
- IFN, interferon
- IFN-I, type 1 interferon
- IFNAR, interferon receptors
- IFNIC, interferon-inducible cells
- IKK, IκB kinase
- IL, interleukin
- IRF3, interferon regulatory factor 3
- ISGs, IRF-3-dependent interferon-stimulated genes
- Inflammation
- LBD, ligand-binding pocket
- LPS, lipopolysaccharides
- MI, myocardial infarction
- MLKL, mixed lineage kinase domain-like protein
- MST1, mammalian Ste20-like kinases 1
- Metabolic diseases
- Mitochondria
- NAFLD, nonalcoholic fatty liver disease
- NASH, nonalcoholic steatohepatitis
- NF-κB, nuclear factor-kappa B
- NLRP3, NOD-, LRR- and pyrin domain-containing protein 3
- NO2-FA, nitro-fatty acids
- NTase, nucleotidyltransferase
- PDE3B/4, phosphodiesterase-3B/4
- PKA, protein kinase A
- PPI, protein–protein interface
- Poly: I.C, polyinosinic-polycytidylic acid
- ROS, reactive oxygen species
- SAVI, STING-associated vasculopathy with onset in infancy
- SNPs, single nucleotide polymorphisms
- STIM1, stromal interaction molecule 1
- STING
- STING, stimulator of interferon genes
- Ser, serine
- TAK1, transforming growth factor β-activated kinase 1
- TBK1, TANK-binding kinase 1
- TFAM, mitochondrial transcription factor A
- TLR, Toll-like receptors
- TM, transmembrane
- TNFα, tumor necrosis factor-alpha
- TRAF6, tumor necrosis factor receptor-associated factor 6
- TREX1, three prime repair exonuclease 1
- YAP1, Yes-associated protein 1
- cGAMP, 2′,3′-cyclic GMP–AMP
- cGAS
- cGAS, cyclic GMP–AMP synthase
- dsDNA, double-stranded DNA
- hSTING, human stimulator of interferon genes
- mTOR, mammalian target of rapamycin
- mtDNA, mitochondrial DNA
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Ou L, Zhang A, Cheng Y, Chen Y. The cGAS-STING Pathway: A Promising Immunotherapy Target. Front Immunol 2021; 12:795048. [PMID: 34956229 PMCID: PMC8695770 DOI: 10.3389/fimmu.2021.795048] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 11/22/2021] [Indexed: 01/07/2023] Open
Abstract
With the continuous development of immunotherapy, researchers have paid more attention to the specific immune regulatory mechanisms of various immune responses in different diseases. As a novel and vital innate immune signal pathway, the cGAS-STING signal pathway activated by nucleic acid substances, interplays with other immune responses, by which it participates in regulating cancer, autoimmune and inflammatory diseases, microbial and parasitic infectious diseases, and other diseases. With the exception of its role in innate immunity, the growing list of researches demonstrated expanding roles of the cGAS-STING signal pathway in bridging the innate immunity (macrophage polarization) with the adaptive immunity (T lymphocytes differentiation). Macrophages and T lymphocytes are the most representative cells of innate immunity and adaptive immunity, respectively. Their polarization or differentiation are involved in the pathogenesis and progression of various diseases. Here we mainly summarized recent advanced discoveries of how the cGAS-STING signal pathway regulated macrophages polarization and T lymphocytes differentiation in various diseases and vaccine applications, providing a promising direction for the development and clinical application of immunotherapeutic strategies for related diseases.
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Affiliation(s)
- Liang Ou
- Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, China
| | - Ao Zhang
- Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, China
| | - Yuxing Cheng
- Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, China
| | - Ying Chen
- Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, China
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Bao T, Liu J, Leng J, Cai L. The cGAS-STING pathway: more than fighting against viruses and cancer. Cell Biosci 2021; 11:209. [PMID: 34906241 PMCID: PMC8670263 DOI: 10.1186/s13578-021-00724-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 12/02/2021] [Indexed: 01/07/2023] Open
Abstract
In the classic Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway, downstream signals can control the production of type I interferon and nuclear factor kappa-light-chain-enhancer of activated B cells to promote the activation of pro-inflammatory molecules, which are mainly induced during antiviral responses. However, with progress in this area of research, studies focused on autoimmune diseases and chronic inflammatory conditions that may be relevant to cGAS-STING pathways have been conducted. This review mainly highlights the functions of the cGAS-STING pathway in chronic inflammatory diseases. Importantly, the cGAS-STING pathway has a major impact on lipid metabolism. Different research groups have confirmed that the cGAS-STING pathway plays an important role in the chronic inflammatory status in various organs. However, this pathway has not been studied in depth in diabetes and diabetes-related complications. Current research on the cGAS-STING pathway has shown that the targeted therapy of diseases that may be caused by inflammation via the cGAS-STING pathway has promising outcomes.
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Affiliation(s)
- Terigen Bao
- Department of Geriatrics, The First Hospital of Jilin University, Changchun, 130021, China
- Department of Pediatrics, The Pediatric Research Institute, The University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Jia Liu
- Department of Geriatrics, The First Hospital of Jilin University, Changchun, 130021, China
| | - Jiyan Leng
- Department of Geriatrics, The First Hospital of Jilin University, Changchun, 130021, China.
| | - Lu Cai
- Department of Pediatrics, The Pediatric Research Institute, The University of Louisville School of Medicine, Louisville, KY, 40292, USA
- Departments of Pharmacology and Toxicology, The University of Louisville School of Medicine, Louisville, KY, USA
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Badal D, Sachdeva N, Maheshwari D, Basak P. Role of nucleic acid sensing in the pathogenesis of type 1 diabetes. World J Diabetes 2021; 12:1655-1673. [PMID: 34754369 PMCID: PMC8554372 DOI: 10.4239/wjd.v12.i10.1655] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/22/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
During infections, nucleic acids of pathogens are also engaged in recognition via several exogenous and cytosolic pattern recognition receptors, such as the toll-like receptors, retinoic acid inducible gene-I-like receptors, and nucleotide-binding and oligomerization domain-like receptors. The binding of the pathogen-derived nucleic acids to their corresponding sensors initiates certain downstream signaling cascades culminating in the release of type-I interferons (IFNs), especially IFN-α and other cytokines to induce proinflammatory responses towards invading pathogens leading to their clearance from the host. Although these sensors are hardwired to recognize pathogen associated molecular patterns, like viral and bacterial nucleic acids, under unusual physiological conditions, such as excessive cellular stress and increased apoptosis, endogenous self-nucleic acids like DNA, RNA, and mitochondrial DNA are also released. The presence of these self-nucleic acids in extranuclear compartments or extracellular spaces or their association with certain proteins sometimes leads to the failure of discriminating mechanisms of nucleic acid sensors leading to proinflammatory responses as seen in autoimmune disorders, like systemic lupus erythematosus, psoriasis and to some extent in type 1 diabetes (T1D). This review discusses the involvement of various nucleic acid sensors in autoimmunity and discusses how aberrant recognition of self-nucleic acids by their sensors activates the innate immune responses during the pathogenesis of T1D.
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Affiliation(s)
- Darshan Badal
- Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Naresh Sachdeva
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Deep Maheshwari
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Preetam Basak
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
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Abstract
Innate immunity is regulated by a broad set of evolutionary conserved receptors to finely probe the local environment and maintain host integrity. Besides pathogen recognition through conserved motifs, several of these receptors also sense aberrant or misplaced self-molecules as a sign of perturbed homeostasis. Among them, self-nucleic acid sensing by the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway alerts on the presence of both exogenous and endogenous DNA in the cytoplasm. We review recent literature demonstrating that self-nucleic acid detection through the STING pathway is central to numerous processes, from cell physiology to sterile injury, auto-immunity and cancer. We address the role of STING in autoimmune diseases linked to dysfunctional DNAse or related to mutations in DNA sensing pathways. We expose the role of the cGAS/STING pathway in inflammatory diseases, neurodegenerative conditions and cancer. Connections between STING in various cell processes including autophagy and cell death are developed. Finally, we review proposed mechanisms to explain the sources of cytoplasmic DNA.
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Affiliation(s)
| | - Nicolas Riteau
- Experimental and Molecular Immunology and Neurogenetics Laboratory (INEM), Centre National de la Recherche Scientifique (CNRS), UMR7355 and University of Orleans, Orleans, France
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Krupa A, Kowalska I. The Kynurenine Pathway-New Linkage between Innate and Adaptive Immunity in Autoimmune Endocrinopathies. Int J Mol Sci 2021; 22:9879. [PMID: 34576041 PMCID: PMC8469440 DOI: 10.3390/ijms22189879] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/09/2021] [Accepted: 09/10/2021] [Indexed: 12/18/2022] Open
Abstract
The kynurenine pathway (KP) is highly regulated in the immune system, where it promotes immunosuppression in response to infection or inflammation. Indoleamine 2,3-dioxygenase 1 (IDO1), the main enzyme of KP, has a broad spectrum of activity on immune cells regulation, controlling the balance between stimulation and suppression of the immune system at sites of local inflammation, relevant to a wide range of autoimmune and inflammatory diseases. Various autoimmune diseases, among them endocrinopathies, have been identified to date, but despite significant progress in their diagnosis and treatment, they are still associated with significant complications, morbidity, and mortality. The precise cellular and molecular mechanisms leading to the onset and development of autoimmune disease remain poorly clarified so far. In breaking of tolerance, the cells of the innate immunity provide a decisive microenvironment that regulates immune cells' differentiation, leading to activation of adaptive immunity. The current review provided a comprehensive presentation of the known role of IDO1 and KP activation in the regulation of the innate and adaptive arms of the immune system. Significant attention has been paid to the immunoregulatory role of IDO1 in the most prevalent, organ-specific autoimmune endocrinopathies-type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis.
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Affiliation(s)
- Anna Krupa
- Department of Internal Medicine and Metabolic Diseases, Medical University of Bialystok, M. Sklodowskiej-Curie 24A, 15-276 Bialystok, Poland
| | - Irina Kowalska
- Department of Internal Medicine and Metabolic Diseases, Medical University of Bialystok, M. Sklodowskiej-Curie 24A, 15-276 Bialystok, Poland
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11
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Akazawa S, Mackin L, Jhala G, Fynch S, Catterall T, Selck C, Graham KL, Krishnamurthy B, Pappas EG, Kwong CTJ, Sutherland APR, Kay TWH, Brodnicki TC, Thomas HE. Deficiency of the innate immune adaptor STING promotes autoreactive T cell expansion in NOD mice. Diabetologia 2021; 64:878-889. [PMID: 33483762 DOI: 10.1007/s00125-020-05378-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 11/17/2020] [Indexed: 01/07/2023]
Abstract
AIMS/HYPOTHESIS Stimulator of IFN genes (STING) is a central hub for cytosolic nucleic acid sensing and its activation results in upregulation of type I IFN production in innate immune cells. A type I IFN gene signature seen before the onset of type 1 diabetes has been suggested as a driver of disease initiation both in humans and in the NOD mouse model. A possible source of type I IFN is through activation of the STING pathway. Recent studies suggest that STING also has antiproliferative and proapoptotic functions in T cells that are independent of IFN. To investigate whether STING is involved in autoimmune diabetes, we examined the impact of genetic deletion of STING in NOD mice. METHODS CRISPR/Cas9 gene editing was used to generate STING-deficient NOD mice. Quantitative real-time PCR was used to assess the level of type I IFN-regulated genes in islets from wild-type and STING-deficient NOD mice. The number of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)206-214-specific CD8+ T cells was determined by magnetic bead-based MHC tetramer enrichment and flow cytometry. The incidence of spontaneous diabetes and diabetes after adoptive transfer of T cells was determined. RESULTS STING deficiency partially attenuated the type I IFN gene signature in islets but did not suppress insulitis. STING-deficient NOD mice accumulated an increased number of IGRP206-214-specific CD8+ T cells (2878 ± 642 cells in NOD.STING-/- mice and 728.8 ± 196 cells in wild-type NOD mice) in peripheral lymphoid tissue, associated with a higher incidence of spontaneous diabetes (95.5% in NOD.STING-/- mice and 86.2% in wild-type NOD mice). Splenocytes from STING-deficient mice rapidly induced diabetes after adoptive transfer into irradiated NOD recipients (median survival 75 days for NOD recipients of NOD.STING-/- mouse splenocytes and 121 days for NOD recipients of NOD mouse splenocytes). CONCLUSIONS/INTERPRETATION Data suggest that sensing of endogenous nucleic acids through the STING pathway may be partially responsible for the type I IFN gene signature but not autoimmunity in NOD mice. Our results show that the STING pathway may play an unexpected intrinsic role in suppressing the number of diabetogenic T cells.
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Affiliation(s)
- Satoru Akazawa
- St Vincent's Institute, Fitzroy, VIC, Australia
- Department of Endocrinology and Metabolism, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | | | | | | | | | | | - Kate L Graham
- St Vincent's Institute, Fitzroy, VIC, Australia
- The University of Melbourne, Department of Medicine, St Vincent's Hospital, Fitzroy, VIC, Australia
| | - Balasubramanian Krishnamurthy
- St Vincent's Institute, Fitzroy, VIC, Australia
- The University of Melbourne, Department of Medicine, St Vincent's Hospital, Fitzroy, VIC, Australia
| | | | - Chun-Ting J Kwong
- St Vincent's Institute, Fitzroy, VIC, Australia
- The University of Melbourne, Department of Medicine, St Vincent's Hospital, Fitzroy, VIC, Australia
| | - Andrew P R Sutherland
- St Vincent's Institute, Fitzroy, VIC, Australia
- The University of Melbourne, Department of Medicine, St Vincent's Hospital, Fitzroy, VIC, Australia
| | - Thomas W H Kay
- St Vincent's Institute, Fitzroy, VIC, Australia
- The University of Melbourne, Department of Medicine, St Vincent's Hospital, Fitzroy, VIC, Australia
| | - Thomas C Brodnicki
- St Vincent's Institute, Fitzroy, VIC, Australia
- The University of Melbourne, Department of Medicine, St Vincent's Hospital, Fitzroy, VIC, Australia
| | - Helen E Thomas
- St Vincent's Institute, Fitzroy, VIC, Australia.
- The University of Melbourne, Department of Medicine, St Vincent's Hospital, Fitzroy, VIC, Australia.
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12
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Innate immune receptors in type 1 diabetes: the relationship to cell death-associated inflammation. Biochem Soc Trans 2021; 48:1213-1225. [PMID: 32510139 DOI: 10.1042/bst20200131] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 05/15/2020] [Accepted: 05/19/2020] [Indexed: 12/17/2022]
Abstract
The importance of innate immunity in host defense and inflammatory responses has been clearly demonstrated after the discovery of innate immune receptors such as Toll-like receptors (TLRs) or Nucleotide-binding oligomerization domain-containing protein (Nod)-like receptors (NLRs). Innate immunity also plays a critical role in diverse pathological conditions including autoimmune diseases such as type 1 diabetes (T1D). In particular, the role of a variety of innate immune receptors in T1D has been demonstrated using mice with targeted disruption of such innate immune receptors. Here, we discuss recent findings showing the role of innate immunity in T1D that were obtained mostly from studies of genetic mouse models of innate immune receptors. In addition, the role of innate immune receptors involved in the pathogenesis of T1D in sensing death-associated molecular patterns (DAMPs) released from dead cells or pathogen-associated molecular patterns (PAMPs) will also be covered. Elucidation of the role of innate immune receptors in T1D and the nature of DAMPs sensed by such receptors may lead to the development of new therapeutic modalities against T1D.
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13
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Smith JA. STING, the Endoplasmic Reticulum, and Mitochondria: Is Three a Crowd or a Conversation? Front Immunol 2021; 11:611347. [PMID: 33552072 PMCID: PMC7858662 DOI: 10.3389/fimmu.2020.611347] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 12/04/2020] [Indexed: 12/20/2022] Open
Abstract
The anti-viral pattern recognition receptor STING and its partnering cytosolic DNA sensor cGAS have been increasingly recognized to respond to self DNA in multiple pathologic settings including cancer and autoimmune disease. Endogenous DNA sources that trigger STING include damaged nuclear DNA in micronuclei and mitochondrial DNA (mtDNA). STING resides in the endoplasmic reticulum (ER), and particularly in the ER-mitochondria associated membranes. This unique location renders STING well poised to respond to intracellular organelle stress. Whereas the pathways linking mtDNA and STING have been addressed recently, the mechanisms governing ER stress and STING interaction remain more opaque. The ER and mitochondria share a close anatomic and functional relationship, with mutual production of, and inter-organelle communication via calcium and reactive oxygen species (ROS). This interdependent relationship has potential to both generate the essential ligands for STING activation and to regulate its activity. Herein, we review the interactions between STING and mitochondria, STING and ER, ER and mitochondria (vis-à-vis calcium and ROS), and the evidence for 3-way communication.
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Affiliation(s)
- Judith A Smith
- Department of Pediatrics and Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, United States
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14
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Gogoi H, Mansouri S, Jin L. The Age of Cyclic Dinucleotide Vaccine Adjuvants. Vaccines (Basel) 2020; 8:E453. [PMID: 32823563 PMCID: PMC7563944 DOI: 10.3390/vaccines8030453] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 08/10/2020] [Accepted: 08/12/2020] [Indexed: 02/07/2023] Open
Abstract
As prophylactic vaccine adjuvants for infectious diseases, cyclic dinucleotides (CDNs) induce safe, potent, long-lasting humoral and cellular memory responses in the systemic and mucosal compartments. As therapeutic cancer vaccine adjuvants, CDNs induce potent anti-tumor immunity, including cytotoxic T cells and NK cells activation that achieve durable regression in multiple mouse models of tumors. Clinical trials are ongoing to fulfill the promise of CDNs (ClinicalTrials.gov: NCT02675439, NCT03010176, NCT03172936, and NCT03937141). However, in October 2018, the first clinical data with Merck's CDN MK-1454 showed zero activity as a monotherapy in patients with solid tumors or lymphomas (NCT03010176). Lately, the clinical trial from Aduro's CDN ADU-S100 monotherapy was also disappointing (NCT03172936). The emerging hurdle in CDN vaccine development calls for a timely re-evaluation of our understanding on CDN vaccine adjuvants. Here, we review the status of CDN vaccine adjuvant research, including their superior adjuvant activities, in vivo mode of action, and confounding factors that affect their efficacy in humans. Lastly, we discuss the strategies to overcome the hurdle and advance promising CDN adjuvants in humans.
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Affiliation(s)
| | | | - Lei Jin
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL 32610, USA; (H.G.); (S.M.)
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15
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Lemos H, Ou R, McCardle C, Lin Y, Calver J, Minett J, Chadli A, Huang L, Mellor AL. Overcoming resistance to STING agonist therapy to incite durable protective antitumor immunity. J Immunother Cancer 2020; 8:e001182. [PMID: 32847988 PMCID: PMC7451475 DOI: 10.1136/jitc-2020-001182] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/23/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Activating the Stimulator of Interferon Genes (STING) adaptor incites antitumor immunity against immunogenic tumors in mice, prompting clinical trials to test STING activators. However, STING signaling in the tumor microenvironment (TME) during development of Lewis lung carcinoma (LLC) suppresses antitumor immunity to promote tumor growth. We hypothesized that local immune balance favoring suppression of antitumor immunity also attenuates antitumor responses following STING activation. The purpose of this study was to evaluate how STING activation impacts antitumor responses in mice bearing LLC tumors. METHODS Mice bearing established LLC tumors were treated with synthetic cyclic diadenyl monophosphate (CDA) to activate STING. Mice were monitored to assess LLC tumor growth, survival and protective antitumor immunity. Transcriptional and metabolic analyses were used to identify pathways responsive to CDA, and mice were co-treated with CDA and drugs that disrupt these pathways. RESULTS CDA slowed LLC tumor growth but most CDA-treated mice (77%) succumbed to tumor growth. No evidence of tumor relapse was found in surviving CDA-treated mice at experimental end points but mice were not immune to LLC challenge. CDA induced rapid increase in immune regulatory pathways involving programmed death-1 (PD-1), indoleamine 2,3 dioxygenase (IDO) and cyclooxygenase-2 (COX2) in the TME. PD-1 blockade enhanced antitumor responses to CDA and increased mouse survival but mice did not eliminate primary tumor burdens. Two IDO inhibitor drugs had little or no beneficial effects on antitumor responses to CDA. A third IDO inhibitor drug synergized with CDA to enhance tumor control and survival but mice did not eliminate primary tumor burdens. In contrast, co-treatments with CDA and the COX2-selective inhibitor celecoxib controlled tumor growth, leading to uniform survival without relapse, and mice acquired resistance to LLC re-challenge and growth of distal tumors not exposed directly to CDA. Thus, mice co-treated with CDA and celecoxib acquired stable and systemic antitumor immunity. CONCLUSIONS STING activation incites potent antitumor responses and boosts local immune regulation to attenuate antitumor responses. Blocking STING-responsive regulatory pathways synergizes with CDA to enhance antitumor responses, particularly COX2 inhibition. Thus, therapy-induced resistance to STING may necessitate co-treatments to disrupt regulatory pathways responsive to STING in patients with cancer.
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Affiliation(s)
- Henrique Lemos
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
| | - Rong Ou
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
| | - Caroline McCardle
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
| | - Yijun Lin
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
| | - Jessica Calver
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
| | - Jack Minett
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
| | - Ahmed Chadli
- Georgia Cancer Center, Augusta University Medical College of Georgia, Augusta, Georgia, USA
| | - Lei Huang
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
| | - Andrew L Mellor
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
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16
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Pan W, Zheng X, Chen G, Su L, Luo S, Wang W, Ye S, Weng J, Min Y. Nanotechnology's application in Type 1 diabetes. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2020; 12:e1645. [PMID: 32558337 DOI: 10.1002/wnan.1645] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/17/2020] [Accepted: 04/17/2020] [Indexed: 12/16/2022]
Abstract
Type 1 diabetes mellitus (T1D) is an autoimmune disease caused by the immune system attacking islet cells. T1D, with a long prediabetes period, and the incidence of T1D increases with age during childhood and peaks at 10-14 years. And once it gets overt, it requires lifelong insulin replace treatment. Therefore, the diagnosis of early-stage T1D and effective treatments are important for the management of T1D patients. The imaging methods, such as magnetic resonance imaging (MRI) and so on, were applied in diagnosis of the early stage T1D and its development tracking. The addition of nanomaterials, especially in MRI, can improve the quality of T1D imaging for the diagnosis of T1D at early stage and cause less harm to human body. Meantime, among various treatment options, islet transplantation and immunotherapy are promising, effective, and less independent on insulin. The addition of nanotechnology can effectively reduce the attack of the immune system on drugs and cells, making the therapeutic drug more targeted in the body and prolonging the action time between drugs and cells, thus its addition makes these therapy safer and more efficient. In this review, we attempt to summarize the recent advances in the development of nanotechnology advances of T1D including using nanomaterials for the diagnosis and immunological imaging of T1D, protecting the transplanted islet cells from immune system attack, and delivering relevant molecules to targeted immunocytes. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Emerging Technologies Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement.
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Affiliation(s)
- Wen Pan
- Department of Endocrinology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, China.,CAS Key Lab of Soft Matter Chemistry, University of Science and Technology of China, Hefei, China.,Department of Chemistry, University of Science and Technology of China, Hefei, China
| | - Xueying Zheng
- Department of Endocrinology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, China
| | - Guiyuan Chen
- Department of Endocrinology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, China.,CAS Key Lab of Soft Matter Chemistry, University of Science and Technology of China, Hefei, China.,Department of Chemistry, University of Science and Technology of China, Hefei, China
| | - Lanhong Su
- Department of Endocrinology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, China.,CAS Key Lab of Soft Matter Chemistry, University of Science and Technology of China, Hefei, China.,Department of Chemistry, University of Science and Technology of China, Hefei, China
| | - Sihui Luo
- Department of Endocrinology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, China
| | - Wei Wang
- Department of Endocrinology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, China
| | - Shandong Ye
- Department of Endocrinology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, China
| | - Jianping Weng
- Department of Endocrinology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, China.,Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yuanzeng Min
- Department of Endocrinology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, China.,CAS Key Lab of Soft Matter Chemistry, University of Science and Technology of China, Hefei, China.,Department of Chemistry, University of Science and Technology of China, Hefei, China.,Department of Bio-X Interdisciplinary Science at Hefei National Laboratory (HFNL) for Physical Science at the Microscale, University of Science and Technology of China, Hefei, China
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Diabetic Foot Ulcers: Current Advances in Antimicrobial Therapies and Emerging Treatments. Antibiotics (Basel) 2019; 8:antibiotics8040193. [PMID: 31652990 PMCID: PMC6963879 DOI: 10.3390/antibiotics8040193] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 10/16/2019] [Accepted: 10/17/2019] [Indexed: 12/23/2022] Open
Abstract
Diabetic foot ulcers (DFUs) are very important diabetes-related lesions that can lead to serious physical consequences like amputations of limbs and equally severe social, psychological, and economic outcomes. It is reported that up to 25% of patients with diabetes develop a DFU in their lifetime, and more than half of them become infected. Therefore, it is essential to manage infection and ulcer recovery to prevent negatives outcomes. The available information plays a significant role in keeping both physicians and patients aware of the emerging therapies against DFUs. The purpose of this review is to compile the currently available approaches in the managing and treatment of DFUs, including molecular and regenerative medicine, antimicrobial and energy-based therapies, and the use of plant extracts, antimicrobial peptides, growth factors, ozone, devices, and nano-medicine, to offer an overview of the assessment of this condition.
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