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Review
. 2024 Feb 2:12:tkad050.
doi: 10.1093/burnst/tkad050. eCollection 2024.

The cGAS-STING pathway: a therapeutic target in diabetes and its complications

Wenjie He  1   2 , Xingrui Mu  1   2 , Xingqian Wu  1   2 , Ye Liu  1   2 , Junyu Deng  1   2 , Yiqiu Liu  1   2 , Felicity Han  3 , Xuqiang Nie  1   2   3   4
Affiliations
Review

The cGAS-STING pathway: a therapeutic target in diabetes and its complications

Wenjie He et al. Burns Trauma. .

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.

Keywords: Cyclic GMP-AMP synthase; Diabetic liver disease; Diabetic wound; Endoplasmic reticulum stress; Pyroptosis; Reprogramming; STING; inflammation.

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Conflict of interest statement

None declared.

Figures

Figure 1
Figure 1
Molecular mechanism of the cGAS-STING pathway. Bacteria and viruses, or some DAMPs, produce abnormal DNA that activates cGAS, producing cGAMP. cGAMP binds to STING transmembrane protein on the endoplasmic reticulum, a process inhibited by spongy cGAMP-STING-TBK1. After being activated by cGAMP, STING forms dimers and recruits TBK1 for ubiquitination. However, this ubiquitination is blocked by nitro-fatty acids, hERK2 and Mtp53. After activation, the connection of STING to STIM1 is cut off, and STING is transferred to the ERGIC together with TBK1, which in turn undergoes trans-autophosphorylation activation of TBK1, followed by tetramerization of STING to provide a phosphorylation site for IRF3 and subsequent phosphorylation of IRF3 by TBK1, producing IFN. Additionally, the NF-κB pathway is also activated by TBK1. Some inflammatory factors produced by these processes can lead to the production of senescence phenotype and the infiltration of inflammatory cells. cGAS cyclic GMP-AMP synthase, B/A DNA binding site B/A, C DNA binding site C, cGAMP 2′3′cyclic GMP–AMP, STING stimulator of interferon genes, TBK1 TANK-binding kinase 1, ULD ubiquitin-like domain, SDD scaffold/dimerization domain, KD kinase domain, IRF3 interferon regulatory factor 3, DAMPS damage-related molecular patterns, hERK2 human extracellular signal-regulated kinase 2, Mtp53 mutated p53, STIM1 stromal interaction molecule 1, ERGIC ER-Golgi intermediate compartment, TRAF TNF receptor associated factor, TLR toll-like receptor, NEMO NF-κB essential modulator, IFI16 interferon gamma induction 16, IL interleukin, IFN interferon
Figure 2
Figure 2
cGAS-STING pathway and the NF-κB pathway. DNA damage can be recognized by ATM, PARP-1 and c32/56, leading to activation of ubiquitination of STING or NEMO, resulting in activation of the NF-κB signaling pathway. TBK1 may also induce activation of IKK, which activates NF-κB. in addition, TBK1 plays a dual role in metabolism. During energy consumption, the AMPK signaling pathway can activate TBK1 via ULK1, which in turn acts as a feedback system to inhibit AMPK, thereby suppressing caloric expenditure. Over-activated TBK1 in turn suppresses inflammation and insulin resistance by inhibiting obesity-mediated activation of NIK and NF-κB. ATM ataxia telangiectasia mutated, PARP-1 poly (ADP-ribose) polymerase1, STING stimulator of interferon genes, TRAF TNF receptor associated factor, IKK inhibitor of kappa B kinase, IκB inhibitory nuclear factor- κB, TAK1 transforming growth factor-beta-activated kinase 1, NIK NF-κB-inducing kinase, AMPK AMP-activated protein kinase, ULK1 UNC-52-like kinase 1, NEMO NF-κB essential modulator, TRIM tripartite motif, K63 lysine 63, cGAS cyclic GMP-AMP synthase
Figure 3
Figure 3
cGAS-STING and JAK–STAT pathways. JAK is activated after receiving the ligand. When the ligand leptin produced by adipocytes is transmitted to the brain, the brain will transmit the signal to promote energy metabolism and reduce appetite. When the ligand is IFN produced by the cGAS-STING pathway, cascade reactions will generate IFN-I/III and finally generate SASP; this pathway is inhibited by cytokine SOCS1/3 and USP18. Furthermore, in diabetes, JAK–STAT activation will lead to decreased insulin sensitivity and obesity-related inflammation, but ABT317 and RNase7 can inhibit it. cGAS cyclic GMP-AMP synthase, cGAMP 2′3′cyclic GMP–AMP, STING stimulator of interferon genes, TBK1 TANK-binding kinase 1, IRF3 interferon regulatory factor 3, JAK Janus kinase, ABT 317 a selective inhibitor of JAK1, TYK2 tyrosine kinase 2, STAT signal transducer and activator of transcription, IFN interferon, SOCS cytokine signal transduction inhibitor, USP18 ubiquitin-specific peptidase 18, SASP senescence-associated secretory phenotype, cGAS-STING cyclic GMP-AMP synthase-stimulator of interferon genes
Figure 4
Figure 4
Other media for activating STING. (a) IFI16 and IFI204 are also involved in the cGAS-STING signaling pathway, which enhances the ability of cGAS to bind DNA and is required for STING activation as a means to enhance IRF3 and NF-κB activation. In turn, there is also negative feedback regulation between IFI16 and cGAS-STING, i.e., excess product IFN promotes ubiquitinated degradation of IFI16 by the proteasome. Finally, IFI16 also promotes the activation of p53 and p-RB, which leads to the production of SASP, resulting in cellular senescence. (b) As a mediator of DSB repair, DNA-PK activates STING but inhibits cGAS, resulting in DNA-PK-STING-IRF3 activation. cGAS cyclic GMP-AMP synthase, cGAMP 2′3′cyclic GMP–AMP, STING stimulator of interferon genes, TBK1 TANK-binding kinase 1, IRF3 interferon regulatory factor 3, IFI16 interferon-inducible 16, IFI204 interferon gamma induction 204, Ub ubiquitination, p53 tumor protein P53, pRB phosphorylated retinoblastoma, SASP senescence-associated secretory phenotype, TRAF TNF receptor-associated factor, DSB DNA double-strand breaks, DNA-PKcs DNA-dependent protein kinase
Figure 5
Figure 5
Relationship between cGAS-STING and ERS in diabetic wounds. (a) When unfolded proteins increase within the ER, it causes ERS, and the main initiating form of ERS is UPR, and the UPR reaction mainly consists of three reactions, i.e., PERK-EIF2A, IRE1α, and ATF6. When an increase in unfolded proteins is detected, the BIP segregates and leads to activation of the three transmembrane proteins of PERK, IRE1α, and ATF6, which ultimately leads to apoptosis and autophagy reaction occurrence. (b) Abnormal over-activation of IL-22 or STING induces ERS, which in turn performs UPR, followed by a cascade of events such as ERAD, translational repression, and other events to alleviate ERS. However, when ERS is prolonged, it leads to apoptosis, but mild UPR promotes proper protein folding and facilitates cellular survival. After ERS, ER-phagy occurs, which restores the ER to its original state and recycles catabolic proteins. Autophagy is a cellular emergency program that inhibits apoptosis caused by overactivated ERS. and STAT3 also has this role. Interestingly, STING overactivation also activates ERS and autophagy, but prolonged activation leads to apoptosis. However, ANP inhibited apoptosis or ERS caused by cGAS-STING overactivation. (c) In the presence of 3DG, MGO is readily generated in high glucose microenvironments and subsequently generates AGEs along with DNA short chains and proteins. AGEs activate ERS as does miR-98-5p, and mild ERS facilitates wound healing, however, sustained ERS in diabetic wounds leads to delayed healing. GLO1 inhibits the generation of AGEs through IRE1α, thereby inhibiting ERS. In addition, inhibition of vitamin D, 4-PBA, lys-D-pro-thr, and PTP1B inhibits ERS, thereby promoting diabetic wound healing. cGAS Cyclic GMP-AMP synthase, cGAMP 2′3′cyclic GMP–AMP, STING stimulator of interferon genes, TBK1 TANK-binding kinase 1, IRF3 interferon regulatory factor 3, IFI16 interferon-inducible 16, IFI204 interferon gamma induction 204, ER endoplasmic reticulum, ERS endoplasmic reticulum stress, UPR unfolded protein response, PERK protein kinase RNA-like ER kinase, IRE1α inositol-requiring enzyme 1 α, ATF4/6 activating transcription factor 4/6, TRAF TNF receptor associated factor, ASK1 apoptosis signal regulating kinase 1, JNK1 c-Jun N-terminal kinase 1, CHOP C/EBP homologous protein, ERAD endoplasmic reticulum (ER)-associated degradation, EIF2A eukaryotic initiation factor 2A, S1P site 1protease, S2P site 2 protease, ANP atrial natriuretic polypeptide, SR717 STING agonist, RU 521 selective cGAS inhibitor, STAT3 signal transducer and activator of transcription 3, TNF-α tumor necrosis factor alpha, 4-PBA 4-phenyl butyric acid, AGEs advanced glycation end products, MGO methylglyoxal, 3DG 3-deoxyglucose ketone, GLO1 glyoxalase 1
Figure 6
Figure 6
cGAS-STING and pyroptosis. Oxidative stress leads to the production of mPTP and increases membrane permeability, resulting in the generation of mtDNA. Additionally, bacteria ingested by macrophages can undergo cleavage by guanylate binding proteins, leading to the production of cDNA. These events activate the cGAS-STING pathway, triggering the production of IFN. Abnormal cDNA and IFN are detected in AIM2 inflammasomes, which activate caspase-1 cleavage and AIM2 activation, resulting in the production of GSDMD perforation protein and the subsequent release of potassium ions (K+), ultimately inducing pyroptosis. The released K+ can further activate NLRP3 inflammasomes. Notably, K+ can also inhibit the activity of cGAS-STING during focal cell death by promoting the binding of cGAS to DNA. cGAMP 2′3′Cyclic GMP–AMP, STING stimulator of interferon genes, MPTP mitochondrial permeability transition pore, GBPS guanylate-binding proteins, AIM2 absent in melanoma 2, GSDMD gasdermin D, IRF3 interferon regulatory factor 3, NLRP3 NOD-like receptor thermal protein domain associated protein 3, ASC apoptotic speck protein, ER endoplasmic reticulum, cGAS-STING cyclic GMP-AMP synthase-stimulator of interferon genes
Figure 7
Figure 7
cGAS-STING pathway and metabolic reprogramming. Metabolic reprogramming in macrophages is centered on two TCA cycle breakpoints, namely the cis-aconitate withdrawal point when succinate ACDO1 activity is elevated and IDH is blocked, enabling the conversion of cis-aconitate into itaconic acid. The antimicrobial properties of itaconic acid and its role as a pro-inflammatory mediator are well-established. It can also inhibit STING activation via Nrf2. Additionally, itaconic acid acts as an inhibitor of succinate dehydrogenase, preventing the conversion of succinate into fumarate. This hinders glycolysis as the primary energy metabolism of M1 via HIF-α, which is less efficient than OXPHOS in M2. STING-IFN activation in M2 leads to its reprogramming to M1, but this process can be inhibited by PDK2/4 deficiency, which also rescues obesity-associated insulin resistance. LPS Lipopolysaccharide, TLR Toll-like receptor, CoA acetyl coenzyme A, IDH isocitrate dehydrogenase, M1 pro-inflammatory macrophages, ACOD1 aconitate decarboxylase 1, Nrf2 nuclear factor erythroid 2-related factor 2, STING stimulator of interferon genes, PARPi PARP inhibitor, IFN interferon, M2 anti-inflammatory macrophages, HIF-α hypoxia-inducible factor -α, PDK2/4 pyruvate dehydrogenase kinase 2/4, OXHPOS oxidative phosphorylation, SDH succinate dehydrogenase, cGAS-STING cyclic GMP-AMP synthase-stimulator of interferon genes
Figure 8
Figure 8
cGAS-STING and cell senescence in diabetes. Cell senescence can be caused by various factors, including oxidative stress, replication fork stagnation, telomere damage and aging. The cGAS-STING pathway plays a crucial role in maintaining genetic stability and preventing tumors by detecting and responding to internal disturbances and external enemies. However, in certain chronic inflammatory conditions such as diabetic high-glucose environments, DNA damage can lead to increased cytoplasmic DNA, activating cGAS-STING and triggering an inflammatory response, ultimately accelerating cellular senescence. Several compounds, including ole, DNase 3 (also called TREX1), HT or curcumol, have been shown to reduce SASP production in aging cells by inhibiting the cGAS-STING pathway. Overall, understanding the role of cGAS-STING in cellular senescence and inflammation can have significant implications for developing new therapies for age-related diseases and chronic inflammatory conditions. RS replication stress, OS oxidative stress, rH2AX a protein of DNA damage response, 8oxoG 8-oxo-7,8-dihydroguanine, Rb retinoblastoma, cGAS cyclic GMP-AMP synthase, cGAMP 2′3′cyclic GMP–AMP, STING stimulator of interferon genes, TBK1 TANK-binding kinase 1, IRF interferon regulatory factor 3, CDK1 cyclin-dependent kinase 1, mtDNA mitochondrial DNA, TREX1 DNase 3, DSB DNA double-strand breaks, Abro1 Abraxas brother 1, FANCD2 FA group D2 protein, dsDNA double-stranded DNA, ssDNA single-stranded DNA, RNF8 ring finger protein 8, NHEJ non-homologous end joining, IFI16 interferon-inducible 16, IFN interferon, p53 tumor protein P53, E2F early 2 factor, LA laminin A, LC laminin C, LB1/2 laminin B1/B2, NL nuclear envelope includes the nuclear layer, NPC nuclear pore complex, ER endoplasmic reticulum, NE nuclear envelope, CCF cytosolic chromatin fragment, SASP senescence-associated secretory phenotype, BMA1 brain and muscle Arnt-like protein-1, OLE oleuropein, HT hydroxytyrosol, ROS reactive oxygen species, INK4α p16, Waf1 p21, cGAS-STING cyclic GMP-AMP synthase-stimulator of interferon genes
Figure 9
Figure 9
The role of cGAS-STING pathway in diabetic complications. (a) In DN, the high glucose environment generates large amounts of ROS, which disrupts mitochondrial function and leaks mtDNA to the extracellular compartment, which activates the cGAS-STING pathway and leads to the activation of the downstream NF-κB, JAK-STAT, and NLRP3 inflammatory pathways, resulting in kidney injury. (b) MAFLD belongs to a class of NAFLD caused by excessive FFA accumulation in T2D, MAFLD leads to the development of IR and progression to hepatitis and cirrhosis. In NAFLD, macrophages are able to activate cGAS-STING via EVs and later phosphorylate p62 and TBK1, producing lipotoxicity-induced ubiquitination and large protein inclusions, which are hallmarks of NAFLD, leading to hepatitis and cirrhosis development. (c) AGEs are increased in diabetic myocardium, which can lead to myocardial sclerosis. Oxidative stress is also increased in diabetic myocardium and FFA-associated mitochondrial uncoupling occurs, which all contribute to the development of DC. At the same time, leukocytes such as macrophages begin to activate. At the mechanistic level, db/db mice are fed via HFD, which leads to mtDNA leakage and activation of cGAS-STING as well as the pyroptosis pathway, leading to the development of DC. In contrast, Metrnl was able to inhibit cGAS-STING as well as pyroptosis via ULK1, thereby alleviating DC. (d) In diabetes skin tissues and adipocytes, the high glucose microenvironment will lead to the excessive production of ROS in keratinocytes, destroy mitochondrial function, and lead to the release of mitochondrial DNA into the cytoplasm, thus activating the cGAS-STING pathway, which leads to increased apoptosis, thus inhibiting DWH. Lipotoxicity in adipocytes can also lead to the release of mtDNA, thereby activating the cGAS-STING pathway and leading to obesity type inflammation. DsbA-L can prevent the occurrence of this pathway, thereby inhibiting the aging caused by obesity. STAT1/3 plays two opposite roles in this process. STAT3 can inhibit obesity induced aging, while STAT1 and IFN can promote inflammation caused by cGAS-STING in obesity. In macrophages, JMJD3 causes STING activation and increases M1 polarization, resulting in delayed DWH, which can be inhibited by insulin. PA can also lead to the release of mtDNA from vascular endothelial cells and the activation of cGAS-STING, which can inhibit the HIPPO-YAP classic pathway, thereby inhibiting angiogenesis and slowing down DWH. JMJD3 jumonji domain-containing protein-3, DN Diabetic nephropathy, ROS reactive oxygen species, mtDNA mitochondrial DNA, cGAS cyclic GMP-AMP synthase, cGAMP 2′3′cyclic GMP–AMP, STING stimulator of interferon genes, TBK1 TANK-binding kinase 1, IRF3 interferon regulatory factor 3, T2D type 2 diabetes, FFA free fatty acid, MAFLD metabolic dysfunction-associated fatty liver disease, IR insulin resistance, NAFLD non-alcoholic fatty liver disease, AGEs advanced glycation end products, DC diabetic cardiomyopathy, ULK1 UNC-52-like kinase 1, HFD high-fat diet, ERS endoplasmic reticulum stress, DsbA-L disulfide bond A oxidoreductase-like protein, WAT white adipose tissue, WH wound healing, PA palmitic acid, cGAS-STING cyclic GMP-AMP synthase-stimulator of interferon genes
Figure 10
Figure 10
Regulation of cGAS-STING by metal ions. Both Fe2+ and Zn2+ increase the binding affinity of cGAS to DNA, thereby activating the cGAS-STING pathway. However, the action of Zn2+ can be inhibited by the Zn2+ chelating agent TPEN. Additionally, Zn2+ can increase the production of reactive oxygen species and inhibit autophagy, leading to mitochondrial dysfunction and subsequent activation of the cGAS-STING pathway. The ZnS@BSA (bovine serum albumin) preparation of Zn2+ can also activate the cGAS-STING pathway. Similarly, Mn2+ can enhance the signaling of cGAS-STING by increasing the binding affinity between cGAMP and STING, promoting the release of mtDNA. Furthermore, excessive Ca2+ can cause the opening of the mitochondrial permeability transition pore, allowing mtDNA to escape and activate both the cGAS-STING pathway and NLRP3 inflammasomes. In the endoplasmic reticulum, Ca2+ mediates the transport of STING, blocking the localization of STING, leading to its transportation to the ERGIC and Golgi for activation. cGAS Cyclic GMP-AMP synthase, cGAMP 2′3′cyclic GMP–AMP, STING stimulator of interferon genes, TBK1 TANK-binding kinase 1, IRF3 interferon regulatory factor 3, BSA bovine serum albumin, TPEN a chelator with strong affinities for Zn2+, Fe2+ and Mn2+, mtDNA mitochondrial DNA, oxDNA oxidative DNA, FEN1 flap endonuclease 1, STIM1 STING and protein-matrix interacting molecule 1
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References

    1. Hopfner KP, Hornung V. Molecular mechanisms and cellular functions of cGAS-STING signalling. Nat Rev Mol Cell Biol. 2020;21:501–21. - PubMed
    1. Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nat Immunol. 2015;16:343–53. - PMC - PubMed
    1. Scutigliani EM, Kikkert M. Interaction of the innate immune system with positive-strand RNA virus replication organelles. Cytokine Growth Factor Rev. 2017;37:17–27. - PMC - PubMed
    1. Burdette BE, Esparza AN, Zhu H, Wang S. Gasdermin D in pyroptosis. Acta Pharm Sin B. 2021;11:2768–82. - PMC - PubMed
    1. Mogensen TH. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev. 2009;22:240–73. - PMC - PubMed