Asta Literature Retrieval: Pathophysiology and clinical mechanisms of STING-Associated Vasculopathy with Onset in Infancy. Core disease mechanis...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Characterization of novel TMEM173 mutation with additive IFIH1 risk allele

• Authors: S. Keskitalo, E. Haapaniemi, E. Einarsdottir, K. Rajamäki, H. Heikkilä et al.
• Year: 2018
• Venue: bioRxiv
• URL: https://www.semanticscholar.org/paper/45b005f3a70e06e9fde9d7fd83850daa5e033cc4
• DOI: 10.1101/394353
• Citations: 2
• Summary: A novel gain-of-function G207E STING mutation causing a distinct phenotype with alopecia, photosensitivity, thyroid dysfunction, and STING-associated vasculopathy with onset in infancy (SAVI) - features is reported.
• Evidence snippets:
• Snippet 1 (score: 0.576) > TMEM173 encodes for STING that is a transmembrane protein activated by pathogen or self-derived cytosolic nucleic acids causing its translocation from ER to Golgi, and further to vesicles. Monogenic STING gain-of-function mutations cause early-onset type I interferonopathy, with disease presentation ranging from fatal vasculopathy to mild chilblain lupus. Molecular mechanisms causing the poor phenotypegenotype correlation are presently unclear. Here we report a novel gain-of-function G207E STING mutation causing a distinct phenotype with alopecia, photosensitivity, thyroid dysfunction, and STING-associated vasculopathy with onset in infancy (SAVI) -features; livedo reticularis, nasal septum perforation, facial erythema, bacterial infections and skin vasculitis. Single residue polymorphisms in TMEM173 and an IFIH1 T946 risk allele modify disease presentation in the affected multigeneration family, explaining the varying clinical phenotypes. The G207E mutation causes constitutive activation of inflammation-related pathways in HEK cells, as well as aberrant interferon signature and inflammasome activation in patient PBMCs. Protein-protein interactions further propose impaired cellular trafficking of G207E mutant STING. These findings reveal the molecular landscape of STING and highlight the complex additive effects on the phenotype. BRIEF SUMMARY Novel gain-of-function mutation in TMEM173, associated with single residue polymorphisms in TMEM173 and IFIH1, causes a distinct clinical phenotype with some shared features of SAVI.

[2] Novel TMEM173 Mutation and the Role of Disease Modifying Alleles

• Authors: S. Keskitalo, E. Haapaniemi, E. Einarsdottir, K. Rajamäki, H. Heikkilä et al.
• Year: 2019
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/ee71acfcbfca7dc6c4db8e42e45d4129b2b84b6e
• DOI: 10.3389/fimmu.2019.02770
• PMID: 31866997
• PMCID: 6907089
• Citations: 58
• Influential citations: 3
• Summary: A novel gain-of-function G207E STING mutation causing a distinct phenotype with alopecia, photosensitivity, thyroid dysfunction, and features of STING-associated vasculopathy with onset in infancy (SAVI) is reported.
• Evidence snippets:
• Snippet 1 (score: 0.546) > Upon binding to pathogen or self-derived cytosolic nucleic acids cyclic GMP-AMP synthase (cGAS) triggers the production of cGAMP that further activates transmembrane protein STING. Upon activation STING translocates from ER via Golgi to vesicles. Monogenic STING gain-of-function mutations cause early-onset type I interferonopathy, with disease presentation ranging from fatal vasculopathy to mild chilblain lupus. Molecular mechanisms underlying the variable phenotype-genotype correlation are presently unclear. Here, we report a novel gain-of-function G207E STING mutation causing a distinct phenotype with alopecia, photosensitivity, thyroid dysfunction, and features of STING-associated vasculopathy with onset in infancy (SAVI), such as livedo reticularis, skin vasculitis, nasal septum perforation, facial erythema, and bacterial infections. Polymorphism in TMEM173 and IFIH1 showed variable penetrance in the affected family, implying contribution to varying phenotype spectrum. The G207E mutation constitutively activates inflammation-related pathways in vitro, and causes aberrant interferon signature and inflammasome activation in patient PBMCs. Treatment with Janus kinase 1 and 2 (JAK1/2) inhibitor baricitinib was beneficiary for a vasculitic ulcer, induced hair regrowth and improved overall well-being in one patient. Protein-protein interactions propose impaired cellular trafficking of G207E mutant. These findings reveal the molecular landscape of STING and propose common polymorphisms in TMEM173 and IFIH1 as likely modifiers of the phenotype.

[3] STING-Associated Vasculopathy with Onset in Infancy: A Review Focusing on Pathophysiology and Treatment Options

• Authors: Konstantinos Drougkas, R. Smerla, Charalampos Skarlis, C. Mavragani
• Year: 2023
• Venue: Journal of Molecular Pathology
• URL: https://www.semanticscholar.org/paper/33121206b94aacd2c86b6f879f88c2237a2cd3ba
• DOI: 10.3390/jmp4040024
• Citations: 3
• Influential citations: 2
• Summary: The underlying pathophysiologic mechanisms of SAVI are described, highlighting the main clinical manifestations and discussing the current treatment approaches, and JAK inhibitors can be a valuable therapeutic intervention that hampers disease progression.
• Evidence snippets:
• Snippet 1 (score: 0.543) > STING-associated vasculopathy with onset in infancy (SAVI) is a rare type Ι interferonopathy caused by gain of function mutations in an encoding stimulator of interferon genes (STING) protein 1. SAVI is characterized by neonatal or infantile-onset systemic inflammation, mainly affecting peripheral cutaneous blood vessels, skin, and lungs. The main disease manifestations include recurrent febrile episodes, cough, dyspnea, and failure to thrive, in association with progressive interstitial lung disease, polyarthritis, and cold-induced red violet plaques or papules on fingers, knees, toes, heels, nasal tip, and ears that can lead to distal ulcerations, skin necrosis, tissue loss, and autoamputation. For the management of SAVI, JAK inhibitors can be a valuable therapeutic intervention that hampers disease progression, while conventional immunosuppressive treatments have shown minimal efficacy. This review aims to describe the underlying pathophysiologic mechanisms of SAVI, highlighting the main clinical manifestations and discussing the current treatment approaches.

[4] Mitochondria, Oxidative Stress and Innate Immunity

• Authors: Yuxin Chen, Zhongyang Zhou, Wang Min
• Year: 2018
• Venue: Frontiers in Physiology
• URL: https://www.semanticscholar.org/paper/f35e56376405abfd92cd60fbc308a03bd77c9948
• DOI: 10.3389/fphys.2018.01487
• PMID: 30405440
• PMCID: 6200916
• Citations: 272
• Influential citations: 6
• Summary: The expanding research field of mitochondria and oxidative stress in innate immune system is reviewed to highlight the new mechanistic insights and discuss the pathological relevance of mitochondrial dysregulation induced aberrant innate immune responses in a growing list of sterile inflammatory diseases.
• Evidence snippets:
• Snippet 1 (score: 0.543) > Specifically, Ogg1 −/− macrophages showed increased oxidized mtDNA, cytochrome c, apoptosis, and IL-1 secretion. All these studies highlight NLRP3 as a potential therapeutic target for atherosclerosis (Tumurkhuu et al., 2016). > Chronic inflammation of endothelial cells initiates cardiovascular disease (Liao, 2013). Mitochondrial damage induced by palmitic acid and mitochondrial DNA release activates the STING-IRF3 pathway, which further trigger ICAM-1 expression and endothelial inflammation. Clinical evidence also identified STING-associated vasculopathy with onset in infancy (SAVI), an autoinflammatory disease result from gainof-function mutations of STING (Liu et al., 2014). With the identified STING expression, endothelial cells exposed with cGAMP, the STING ligand, result in cellular activation indicated by elevated inducible nitric oxide synthase (iNOS) and E-selectin followed by apoptosis. Since mutant STING increased level of phosphorylated signal transducer and activator of transcription 1 (STAT1), the elucidation of such mechanism also suggests Janus kinase (JAK) inhibitor as a potential therapeutic strategy for SAVI, which is currently under clinical assessment. STING pathway is also involved in adipose tissue inflammation and insulin resistance. In obese mice triggered by high-fat diet, STING was found in adipose tissue and was actively involved in tissue inflammation and insulin resistance (Mao et al., 2017).

[5] Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI)

• Authors: C. David, M. Frémond
• Year: 2022
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/fe47a2cccda7c53375d0351e42619b3422c71b28
• DOI: 10.3390/cells11030318
• PMID: 35159128
• PMCID: 8834229
• Citations: 61
• Influential citations: 2
• Summary: Recent insights into the pathophysiology of SAVI and the current understanding of self-nucleic acid-mediated lung inflammation in humans are reviewed and an improved understanding of such mechanisms is fundamental to improved future patient management.
• Evidence snippets:
• Snippet 1 (score: 0.533) > STING-associated vasculopathy with onset in infancy (SAVI) is a type I interferonopathy caused by gain-of-function mutations in STING1 encoding stimulator of interferon genes (STING) protein. SAVI is characterized by severe inflammatory lung disease, a feature not observed in previously described type I interferonopathies i.e., Mendelian autoinflammatory disorders defined by constitutive activation of the type I interferon (IFN) pathway. Molecular defects in nucleic acid metabolism or sensing are central to the pathophysiology of these diseases, with such defects occurring at any step of the tightly regulated pathway of type I IFN production and signaling (e.g., exonuclease loss of function, RNA-DNA hybrid accumulation, constitutive activation of adaptor proteins such as STING). Among over 30 genotypes, SAVI and COPA syndrome, whose pathophysiology was recently linked to a constitutive activation of STING signaling, are the only type I interferonopathies presenting with predominant lung involvement. Lung disease is the leading cause of morbidity and mortality in these two disorders which do not respond to conventional immunosuppressive therapies and only partially to JAK1/2 inhibitors. In human silicosis, STING-dependent sensing of self-DNA following cell death triggered by silica exposure has been found to drive lung inflammation in mice and human models. These recent findings support a key role for STING and nucleic acid sensing in the homeostasis of intrinsic pulmonary inflammation. However, mechanisms by which monogenic defects in the STING pathway lead to pulmonary damages are not yet fully elucidated, and an improved understanding of such mechanisms is fundamental to improved future patient management. Here, we review the recent insights into the pathophysiology of SAVI and outline our current understanding of self-nucleic acid-mediated lung inflammation in humans.

[6] Original Article Highlights From This Issue

• Authors: Unknown authors
• Year: 2021
• Venue: The Journal of Allergy and Clinical Immunology. in Practice
• URL: https://www.semanticscholar.org/paper/a2da4d5c70f961447ce1ff3d258bfb2c0ed178d6
• DOI: 10.1016/S2213-2198(21)00007-6
• PMCID: 7928703
• Citations: 5
• Summary: Insight into IPV, a prevalent but underaddressed public health issue, elucidates potential etiologies behind difficult-to-control asthma, and will help to improve tailored evaluation and therapies.
• Evidence snippets:
• Snippet 1 (score: 0.518) > What is already known about this topic? Inborn errors of immunity causing primary immunodeficiencies (PIDs) are prone to diagnostic delay because of their rareness and variable manifestations. Immune dysregulations are important manifestations in defining PIDs, besides increased susceptibility to infections and malignancies. > What does this article add to our knowledge? This paper provides an overview of the immune dysregulations that are most common in specific PIDs, the PIDs that present similarly, and the signs that may help the clinician to differentiate between them. > How does this study impact current management guidelines? This systematic review of the immune dysregulations described in the literature on PIDs should help clinicians to detect and diagnose an underlying PID in certain patients with autoimmune and other inflammatory diseases, including allergies. > Overview of STING-Associated Vasculopathy with Onset in Infancy (SAVI) Among 21 Patients Frémond et al 803 > What is already known about this topic? STING-associated vasculopathy with onset in infancy, caused by gain-of-function mutations in STING1, is typically characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease. Janus kinase (JAK) inhibitors are promising treatment. > What does this article add to our knowledge? Lung disease was constant, leading to early and insidious development of fibrosis, and polyarthritis (including destructive form) with positive rheumatoid factor frequently occurs. Overlapping features with other monogenic interferonopathies may arise. Treatment with ruxolitinib improved clinical features of the disease. > How does this study impact current management guidelines? The extension of STING-associated vasculopathy phenotype warrants careful clinical and genetic screening of patients with apparently isolated skin, lung, or joint inflammation, in particular with early onset, and in the presence of autoantibodies or memory CD8 lymphopenia. Early diagnosis is needed to maximize treatment benefit with JAK inhibitors. > Emerging Causes of Drug-Induced Anaphylaxis: A Review of Anaphylaxis-Associated Reports in the FDA Adverse Event Reporting System (FAERS)

[7] Development of vascular disease models to explore disease causation and pathomechanisms of rare vascular diseases

• Authors: R. Harper, Elisa A Ferrante, M. Boehm
• Year: 2022
• Venue: Seminars in Immunopathology
• URL: https://www.semanticscholar.org/paper/bf1052e47fc5b39e6540c7e5e9b8186583b71f45
• DOI: 10.1007/s00281-022-00925-9
• PMID: 35233690
• PMCID: 8887661
• Citations: 9
• Summary: These emerging vascular disease models are reviewed, how they contribute to the understanding of the pathomechanisms in rare vascular diseases and provide useful platforms for therapeutic discovery.
• Evidence snippets:
• Snippet 1 (score: 0.503) > A critical understanding of the BMPR2 signaling cascade and its components of some mothers against decapentaplegic (SMAD) and non-SMAD proteins have been extensively studied in the pursuit of more effective treatments [66][67][68][69][70][71]. A novel transgenic mouse model has led to insightful pathomechanisms in stimulator of interferon genes (STING)associated vasculopathy with onset in infancy (SAVI), an autoinflammatory disorder caused by a gain-of-function mutation in TMEM173 encoding the STING protein [72]. The overactivation of STING leads to a chronic activation of interferon pathways leading to endothelial dysfunction. This disease affects multiple organs and coupled with its genetic component, rarity, and limitations associated with sample collection from infants is a great candidate to investigate using a mouse vascular disease model. Another rare vascular disease that has seen great advancement in understanding and treatment with the aid of mouse models is sickle cell anemia (SCA) [73,74]. There are currently many clinical trials for SCA underway that target vasoocclusion, inflammation, gene editing, and cell therapy with gene editing, all made possible through the use of proof-ofconcept animal models [74]. > With their genetic simplicity, rare monogenetic vascular diseases are ideal candidates for transgenic mouse models. Despite the known physiological limitations of animal models, they have been proven to show relevant genetic and phenotypic similarities with human disease, particularly following gene modification. Thus, there remains a certain utility for rare vascular disease in vivo models when used in conjunction with patient-specific in vitro platforms. These models are particularly helpful to extensively study pathomechanisms in an integrated multiorgan system as well as for proof-of-concept therapy approaches.

[8] A path towards personalized medicine for autoinflammatory and related diseases

• Authors: Jonathan J. Miner, K. Fitzgerald
• Year: 2023
• Venue: Nature Reviews. Rheumatology
• URL: https://www.semanticscholar.org/paper/2c206588d42bbc73259bf29a895ce91abd1e2acd
• DOI: 10.1038/s41584-022-00904-2
• PMID: 36750685
• PMCID: 9904876
• Citations: 22
• Summary: This Perspective describes how new sequencing technologies combined with careful clinical phenotyping have led to the discovery of rare rheumatic diseases and their corresponding disease-causing mutations, and explores ways in which single-gene mutations, including somatic mutations, are creating opportunities to develop personalized medicines.
• Evidence snippets:
• Snippet 1 (score: 0.498) > CL and their families now feel more hopeful, as mutations in TREX1 pinpoint this protein as a key therapeutic target. Physicians and scientists are now working to define molecular mechanisms of RVCL pathogenesis, and to develop gene therapies to correct the disease-causing mutation, as well as small molecule drugs that preferentially correct defects elicited by the mutant TREX1 protein. > In 2014, another rare disease known as STING-associated vasculopathy with onset in infancy (SAVI) was discovered and reported by the laboratory of Raphaela Goldbach-Mansky at the National Institutes of Health 19 . Patients with SAVI develop severe Raynaud syndrome, vasculopathy with autoamputation of digits, skin rash and pulmonary fibrosis, often within the first year of life 19 . The disease-causing mutation renders STING constitutively active. STING is an important player in the cell-intrinsic innate immune response against viruses and other pathogens 20 . Introduction of the SAVI mutation into animal models using CRISPR/Cas9 technology has confirmed that these STING gain-of-function mutations are indeed pathogenic [21][22][23] . The peripheral blood mononuclear cells of patients with SAVI exhibit constitutive upregulation of type I interferon-stimulated genes, which are one of the most prominent pathways activated downstream of STING 19 . These findings led to the use of JAK inhibitors as a treatment for patients with SAVI, which can reduce signalling downstream of the type I interferon receptor 24 . Unfortunately, JAK inhibition does not always control the progression of this disease 19,[24][25][26] . Studies in mouse models of SAVI have shown that disease progresses normally even in animals lacking the receptor for type I interferons, suggesting that the disease-causing mutations also have type I interferon-independent effects that contribute to disease [21][22][23]27 . Ongoing efforts in the field are aimed at further defining the molecular mechanisms of SAVI pathogenesis as well as the cell types involved in disease initiation, which might eventually lead to even better treatments for SAVI. > In 2015, researchers described another disease called COPA syndrome 28 . Patients with COPA syndrome have mutations in the COPA gene that encodes the α-COP component of the coatome

[9] Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling

• Authors: A. L. Hansen, G. Buchan, Michael Rühl, Kojiro Mukai, S. Salvatore et al.
• Year: 2018
• Venue: Proceedings of the National Academy of Sciences of the United States of America
• URL: https://www.semanticscholar.org/paper/f095fd94b939e9467fecce0b2c3940e39f82b0a8
• DOI: 10.1073/pnas.1806239115
• PMID: 30061387
• PMCID: 6099880
• Citations: 261
• Influential citations: 8
• Summary: It is reported that endogenously formed nitro-fatty acids can covalently modify STING by Nitro-alkylation, and proposed that these lipids could have pharmaceutical potential for treatment of STING-dependent inflammatory diseases.
• Evidence snippets:
• Snippet 1 (score: 0.498) > Significance Several chronic inflammatory conditions have recently been shown to depend on abnormally high activity of the signaling protein stimulator of IFN genes (STING). These conditions include examples from systemic lupus erythematosus, Aicardi–Goutiéres syndrome, and STING-associated vasculopathy with onset in infancy. The involvement of STING in these diseases points to an unmet demand to identify inhibitors of STING signaling, which could form the basis of anti-STING therapeutics. With this report, we identify distinct endogenously formed lipid species as potent inhibitors of STING signaling—and propose that these lipids could have pharmaceutical potential for treatment of STING-dependent inflammatory diseases. The adaptor molecule stimulator of IFN genes (STING) is central to production of type I IFNs in response to infection with DNA viruses and to presence of host DNA in the cytosol. Excessive release of type I IFNs through STING-dependent mechanisms has emerged as a central driver of several interferonopathies, including systemic lupus erythematosus (SLE), Aicardi–Goutières syndrome (AGS), and stimulator of IFN genes-associated vasculopathy with onset in infancy (SAVI). The involvement of STING in these diseases points to an unmet need for the development of agents that inhibit STING signaling. Here, we report that endogenously formed nitro-fatty acids can covalently modify STING by nitro-alkylation. These nitro-alkylations inhibit STING palmitoylation, STING signaling, and subsequently, the release of type I IFN in both human and murine cells. Furthermore, treatment with nitro-fatty acids was sufficient to inhibit production of type I IFN in fibroblasts derived from SAVI patients with a gain-of-function mutation in STING. In conclusion, we have identified nitro-fatty acids as endogenously formed inhibitors of STING signaling and propose for these lipids to be considered in the treatment of STING-dependent inflammatory diseases.

[10] Cell biological insights into human STING variants

• Authors: Shogo Koide, Eisuke Yumoto, Jun Nakayama, Shigeki Higashiyama, Yoshihiko Kuchitsu et al.
• Year: 2025
• Venue: Cell Structure and Function
• URL: https://www.semanticscholar.org/paper/497ae092563f70e752b8066eb63d0c0a24f2f179
• DOI: 10.1247/csf.25020
• PMID: 40368781
• PMCID: 12702684
• Summary: Recent insights into human STING variants and their inflammatory activities are summarized and the distinct activities of the major variants in the context of the pathogenesis of autoinflammatory diseases are revealed.
• Evidence snippets:
• Snippet 1 (score: 0.486) > Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER)-localized transmembrane protein. STING induces type I interferon and inflammatory responses against a variety of double-stranded DNA (dsDNA) viruses, which is critical for limiting their infection and replication. In certain settings where self-DNAs (genomic or mitochondrial DNA) emerge in the cytosol or when intracellular membrane traffic is impaired, STING becomes activated and triggers inflammation, which may contribute to the pathogenesis of various autoinflammatory and neurodegenerative diseases, including COPA syndrome and Parkinson’s disease. The human STING gene exhibits genetic heterogeneity with R232, HAQ (R71H-G230A-R293Q), and H232 being the most common variants, along with population stratification. A very recent study has shown that HAQ, not R232 or H232, mediates complete clinical protection in the pathogenesis of COPA syndrome. These results reveal, for the first time, the distinct activities of the major variants in the context of the pathogenesis of autoinflammatory diseases. Besides these major variants, there exist minor pathogenic STING variants that cause an autoinflammatory disease called STING-associated vasculopathy with onset in infancy (SAVI). This review summarizes recent insights into human STING variants and their inflammatory activities.

[11] cGAS-STING Pathway Performance in the Vulnerable Atherosclerotic Plaque

• Authors: Xueqi Wan, Jinfan Tian, Peng Hao, Kuo Zhou, Jing Zhang et al.
• Year: 2022
• Venue: Aging and Disease
• URL: https://www.semanticscholar.org/paper/15f4884acf15d3eb36c4649fd015dc833e7054b6
• DOI: 10.14336/AD.2022.0417
• PMID: 36465175
• PMCID: 9662268
• Citations: 15
• Summary: It is concluded that STIM1/cGAS-STING is involved in the progression of AS and plaque vulnerability.
• Evidence snippets:
• Snippet 1 (score: 0.485) > The activation of the cGAS-STING pathway accelerated inflammation and heart disease in HFD-fed ApoE-/-mice [56]. On the other hand, inhibiting STING down-regulated TNF-α, IFNα, and IFNβ, and decreased cardiac inflammation [57]. > Recently, several studies found a specialized immune response to be involved in the progression of atheroma plaque formation [58,59]. Interestingly, the cGAS-STING pathway has been elucidated to modulate the cellular immune response to viral and bacterial infections, and STING mutation or excessive STING activation is closely associated with various autoimmune diseases such as STING-associated vasculopathy with onset in infancy SAVI) and systemic Lupus Erythematosus (SLE) [34,60]. These observations indirectly support the connection between the STING pathway and AS plaque rupture.

[12] Small-molecule perturbation profiling reveals a mechanistic link between STING signaling and lipid metabolism in macrophages and dendritic cells

• Authors: Lilah Gmyrek, Jianan Zhang, M. Andrade, Kathryn R. Hillette, Xu Wu et al.
• Year: 2025
• Venue: bioRxiv
• URL: https://www.semanticscholar.org/paper/0048bc7563c6ee64830f6facb434b4c55a3ccc26
• DOI: 10.1101/2025.04.25.650730
• PMID: 41109016
• Summary: Findings reveal a connection between STING signaling and lipid metabolism and opportunities for expanding the toolbox for treating clinical conditions that arise from aberrant STING activity.
• Evidence snippets:
• Snippet 1 (score: 0.484) > Unrestrained STING activation and IFN induction in response to self-DNA can cause immunopathology, as seen in a wide range of genetic disorders and chronic diseases associated with inflammation, autoimmunity, and neurodegeneration. STING-associated vasculopathy with onset in infancy (SAVI) is a case in point: this autoinflammatory disorder with skin and lung manifestations arises from gain-of-function mutations in the STING gene (22). Aberrant mitochondrial retention in erythroid cells drives STING-dependent type I IFN production by macrophages in systemic lupus erythematosus (23). Mutations in the TDP43 and C9ORF72 genes, which are associated with amyotrophic lateral sclerosis and frontotemporal dementia, promote neurodegeneration through excessive STING activation. These mutations activate STING signaling by causing cytoplasmic TDP43 accumulation and TDP43-mediated mitochondrial DNA leakage (24) or by preventing C9ORF72-dependent lysosomal degradation of STING (25). STING activation by mitochondrial DNA in senescent cells has been shown to be a main driver of aging-related inflammation, neurodegeneration, and tissue dysfunction in mice (26). In addition to the well-established molecular events occurring within the cGAS-STING pathway, a diverse array of cellular processes and physiological conditions are expected to exert critical influence on STING activation and the resulting immune responses. Little information is available, however, regarding the wider molecular network in which STING serves its functions in health and disease. > Here, we discover novel interactions between STING signaling and lipid metabolism in macrophages and dendritic cells (DCs). Our study identifies small-molecules inhibitors of distinct lipid metabolic pathways that potently suppress or enhance IFN induction in STING agonist-treated cells. We show that perturbations in lipid metabolism can exert divergent effects on STING signaling in human and mouse cells, a phenomenon likely attributable to the difference of human and mouse STING proteins in their intrinsic capacity for lipid binding.

[13] A Mutation Outside the Dimerization Domain Causing Atypical STING-Associated Vasculopathy With Onset in Infancy

• Authors: Rohit G. Saldanha, Katherine R Balka, Sophia Davidson, Brynn K Wainstein, M. Wong et al.
• Year: 2018
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/16beca5d3864be1af06807a976b982d06e45a7dd
• DOI: 10.3389/fimmu.2018.01535
• PMID: 30038614
• PMCID: 6047589
• Citations: 101
• Influential citations: 2
• Summary: Molecular evidence is provided to support the p.Arg284Ser variant in STING exerting pathogenicity through a gain-of-function mechanism and raises the possibility that variants outside the STING DD may potentially manifest with an atypical SAVI phenotype.
• Evidence snippets:
• Snippet 1 (score: 0.481) > Background Mutations in the gene encoding stimulator of interferon genes (STING) underlie a type I interferon (IFN) associated disease, STING-associated vasculopathy with onset in infancy (SAVI). Patients suffer cutaneous vasculopathy and interstitial lung disease, but are not known to suffer life-threatening infection. Case We describe a child who presented with Pneumocystis jirovecii pneumonia in early life, from which he recovered. He went on to suffer failure to thrive, developmental delay, livedo reticularis, and vesicular rash, but without cutaneous vasculitis, and with normal C-reactive protein and erythrocyte sedimentation rates. At 3 years of age, he developed life-threatening pulmonary hypertension. Methods Whole genome sequencing (WGS) was performed using the Illumina HiSeqX10 platform and the Seave platform was used for bioinformatic analysis. mRNA expression of IFN-stimulated genes and inflammatory cytokines from peripheral blood mononuclear cells was determined by quantitative polymerase chain reaction. Luciferase assay was used to model IFNβ and NF-κB activity in vitro. Results WGS revealed a de novo mutation p.Arg284Ser in STING at an amino acid previously associated with SAVI. Although this mutation did not fall in the dimerization domain (DD), mRNA analysis revealed constitutive IFN-gene activation consistent with an interferonopathy, which correlated to STING activation in vitro. The patient was treated with corticosteroids and the JAK inhibitor Ruxolitinib, resulting in a rapid improvement of pulmonary hypertension, general well-being, and resolution of the IFN gene signature. However, he did go on to evolve a nasal septal erosion suggesting incomplete control of disease. Conclusion This case provides molecular evidence to support the p.Arg284Ser variant in STING exerting pathogenicity through a gain-of-function mechanism. The lack of cutaneous vasculitis or elevated systemic inflammatory markers, and the occurrence of an opportunistic infection are notable, and raise the possibility that variants outside the STING DD may potentially manifest with an atypical SAVI phenotype. Nevertheless, there was

[14] Non-canonical STING–PERK pathway dependent epigenetic regulation of vascular endothelial dysfunction via integrating IRF3 and NF-κB in inflammatory response

• Authors: Xuesong Li, Xiang Chen, Longbin Zheng, Minghong Chen, Yunjia Zhang et al.
• Year: 2023
• Venue: Acta Pharmaceutica Sinica. B
• URL: https://www.semanticscholar.org/paper/e6ff1be690e9e6bb8b444c4880d277a70795b086
• DOI: 10.1016/j.apsb.2023.08.015
• PMID: 38045042
• PMCID: 10692388
• Citations: 54
• Influential citations: 1
• Summary: A non-canonical STING–PERK pathway-dependent epigenetic paradigm in atherosclerosis that integrates IRF3, NF-κB and BRD4 in inflammatory responses is proposed, which provides emerging therapeutic modalities for vascular endothelial dysfunction.
• Evidence snippets:
• Snippet 1 (score: 0.478) > Atherosclerosis, a leading cause of cardiovascular morbidity and mortality, emerges as a significant contemporary public health issue 1 . As a chronic inflammatory disease, endothelial dysfunction is the major initiating factor in the atherogenic process 2,3 . Therefore, identifying the molecular mechanism underlying endothelial dysfunction is an essential step in developing preventive and therapeutic approaches for atherosclerosis. > The abnormal signal transduction associated with cardiovascular diseases (CVDs) has been linked to inflammatory responses. However, the precise mechanism connecting endothelial dysfunction and inflammation during atherosclerosis remains elusive. Recently, numerous evidence has shown the stimulator of interferon genes (STING), a proinflammatory molecule in the cyclic GMPeAMP (cGAMP) synthase (cGAS)eSTING pathway, is a critical signaling molecule in immunity and inflammation 4 . STING signaling-driven inflammation has been implicated in the pathogenesis of many diseases, such as Parkinson's disease, nonalcoholic steatohepatitis, amyotrophic lateral sclerosis and myocardial infarction 5e8 . Shen's group 9 has emphasized the critical role of STING in the rupture of aortic aneurysm and dissection, from the aspects of inflammation and destruction. Gain-of-function mutations in STING have also been identified in STING-associated vasculopathy early onset in infancy and familial inflammatory syndrome with lupus-like manifestations 10 . These findings suggest STING's involvement in vascular disease. However, its role in endothelial dysfunction and atherosclerosis is yet to be determined. By leveraging publicly available microarray data, we found that the expression levels of STING pathwayrelated genes were elevated in patients with plaques, indicating a potential link between the STING pathway and inflammation in atherosclerosis. > The cGASeSTING pathway is activated by recognizing cytoplasmic foreign double-stranded DNA (dsDNA) from DNA viruses, bacteria, or parasites 4,11 . Besides, it can also be triggered by self-DNA, including genomic and mitochondrial DNA (mtDNA), to catalyze the synthesis of cGAMP 12 .

[15] STING-targeting PROTACs: emerging therapeutic tools for enhanced immunotherapy in inflammatory diseases

• Authors: Wenqing Jiang, Xiaoping Yang, Huiying Liu, Chao Wang, Hongxin Niu et al.
• Year: 2025
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/2554ebcf0b8339136a25c749cdc53bdbcd8d818a
• DOI: 10.3389/fimmu.2025.1631132
• PMID: 41030459
• PMCID: 12477151
• Citations: 3
• Summary: A review critically evaluates the rationale for STING degradation, with a comparative analysis of recent PROTAC designs and their pharmacokinetic/pharmacodynamic trade-offs, highlighting strategies to enhance specificity and clinical utility.
• Evidence snippets:
• Snippet 1 (score: 0.475) > Inflammatory diseases constitute a diverse group of disorders characterized by dysregulated immune responses leading to chronic tissue damage and organ dysfunction (1)(2)(3). These conditions, which include rheumatoid arthritis, inflammatory bowel diseases, systemic lupus erythematosus, and various fibrotic disorders, collectively impose a substantial burden on global healthcare systems (4)(5)(6)(7). At the molecular level, many of these diseases share common pathogenic mechanisms involving aberrant activation of innate immune pathways, with the cyclic GMP-AMP synthase (cGAS)-STING axis emerging as a central player in disease pathogenesis (8,9). > The cGAS-STING pathway (Figure 1) serves as a critical DNA sensing mechanism that detects both exogenous pathogen-derived DNA and endogenous DNA resulting from cellular damage or stress (10). Upon activation, STING initiates a cascade of downstream signaling events leading to the production of type I interferons and pro-inflammatory cytokines (11). While this response is essential for host defense against viral and bacterial infections, chronic or inappropriate activation of STING signaling has been implicated in the pathogenesis of numerous autoinflammatory and autoimmune conditions (12). For instance, gain-of-function mutations in STING are responsible for STING-associated vasculopathy with onset in infancy (SAVI), a severe autoinflammatory disorder characterized by systemic inflammation and vascular pathology (13). Similarly, excessive STING activation has been demonstrated in mouse models of lupus and rheumatoid arthritis, where it contributes to disease progression through sustained interferon production (14). > Current therapeutic strategies targeting the STING pathway in inflammatory diseases primarily focus on either inhibiting STING activation (using small molecules like C-176) or blocking downstream interferon signaling (through antibodies targeting interferon receptors or Janus kinase inhibitors) (15)(16)(17).

[16] Single-cell RNA-sequencing of PBMCs from SAVI patients reveals disease-associated monocytes with elevated integrated stress response

• Authors: C. D. Cevins, Laure Delage, M. Batignes, Q. Riller, Marine Luka et al.
• Year: 2023
• Venue: medRxiv
• URL: https://www.semanticscholar.org/paper/2b4972930fd429227d287f0803d2d56c54b30d16
• DOI: 10.1101/2023.04.25.23288913
• Citations: 5
• Summary: A strategy to propose a transcriptomic signature specific of STING activation and independent of type I IFN response is developed, providing a deeper understanding of SAVI at the cellular and molecular levels.
• Evidence snippets:
• Snippet 1 (score: 0.474) > Gain-of-function mutations in STING1, which encodes the Stimulator of Interferon Gene (STING), result in a severe autoinflammatory disease termed STING-associated vasculopathy with onset in infancy (SAVI). Although elevated type I interferon (IFN) production is thought to be the leading cause of the symptoms observed in patients, STING can induce a set of pathways, which roles in the onset and severity of SAVI, remain to be elucidated. To address this point, we compared a single-cell RNA sequencing (scRNA-seq) dataset of peripheral blood mononuclear cells (PBMCs) from SAVI patients to a dataset of healthy PBMCs treated with recombinant IFN-beta. We revealed a loss of mucosal associated invariant T cells and CD56bright natural killer cells in SAVI patients, not observed in IFN-beta-treated PBMC. Patients T cells present markers of early activation, associated with markers of senescence and apoptosis. Inferring cell-to-cell communication from scRNA-seq predicted monocytes as potential drivers of this T cell phenotype. Furthermore, scRNA-seq clustering identified a patient-specific subset of monocytes, expressing a strong integrated stress response (ISR), and high CCL3, CCL4 and IL-6. It also pinpointed to a patient with lower ISR, allowing us to identify a secondary mutation in PERK, recently shown to be activated by STING to trigger the ISR. Finally, based on the identification of this patient-specific subset of monocytes and the exploration of IFN-beta stimulated PBMCs from healthy donors, we developed a strategy to propose a transcriptomic signature specific of STING activation and independent of type I IFN response. Altogether, these results provide a deeper understanding of SAVI at the cellular and molecular levels.

[17] Vasculitis Pathogenesis: Can We Talk About Precision Medicine?

• Authors: S. Ozen, E. Batu
• Year: 2018
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/47e16bd13cb40a719f248e0c87e6d91bf15f0d11
• DOI: 10.3389/fimmu.2018.01892
• PMID: 30154798
• PMCID: 6102378
• Citations: 22
• Summary: Genome-wide association studies (GWAS) data, lessons from monogenic mimics of these diseases, and biomarker studies in immunoglobulin A vasculitis/Henoch–Schönlein purpura, Kawasaki disease, anti-neutrophil cytoplasmic antibody-associated Vasculitis, polyarteritis nodosa (PAN), Takayasu arteritis, and Behçet's disease are reviewed.
• Evidence snippets:
• Snippet 1 (score: 0.474) > Stimulator of interferon genes-associated vasculopathy with onset in infancy is a type I interferonopathy caused by gainof-function mutations in TMEM173 encoding for STING (47). STING hyperfunction results in constitutive transcription of type I interferons (IFNs) which bind to type I IFN receptors and signal through Janus activating kinase/signal transducer and activator of transcription (JAK/STAT) pathway (47,48). > Phenotype of SAVI patients could resemble GPA with severe cutaneous vasculopathy, pulmonary involvement, and ANCA positivity in some patients (49). Recently, Sanchez et al. have shown improvement in SAVI patients with baricitinib which is a selective JAK1 and JAK2 inhibitor (50).

[18] STING: infection, inflammation and cancer

• Authors: G. Barber
• Year: 2015
• Venue: Nature Reviews. Immunology
• URL: https://www.semanticscholar.org/paper/1ed655394c2871f40550f0a374c28ed74a52a03b
• DOI: 10.1038/nri3921
• PMID: 26603901
• PMCID: 5004891
• Citations: 1144
• Influential citations: 33
• Summary: The discovery of the STING (stimulator of interferon genes)-controlled innate immune pathway, which mediates cytosolic DNA-induced signalling events, has recently provided important insights into these processes, opening the way for the development of novel immunization regimes, as well as therapies to treat autoinflammatory disease and cancer.
• Evidence snippets:
• Snippet 1 (score: 0.471) > Alternative polymorphisms in the human TMEM173 gene have been reported to result in a gain-of-function phenotype and are likely to contribute to severe inflammatory disorders. For example, patients suffering from vascular and pulmonary syndrome (VAPS), which is typified by lesions in the cheeks, nose, fingers and toes, were found to have mutations that result in STING hyperactivity 100 . Patients with VAPS were found to exhibit three mutations in exon 5 of TMEM173 (N154S, V155M and V147L). These variants potently stimulated the type I IFN promoter, as determined by in vitro expression studies in 293T cells 100 . Speculatively, these mutations may expedite STING trafficking from the endoplasmic reticulum to the perinuclear region to stimulate cytokine production or may affect STING protein stability, thereby sustaining STING activity 101 . > It is also not yet clear why patients with STING-associated vasculopathy with onset in infancy (referred to as SAVI)which is an autoinflammatory disease caused by genetic mutations that result in STING hyperactivity, even in the absence of cytosolic DNA species -develop the disease. It is possible that STING-induced cytokines may affect endothelial function and aggravate macrophage activity in blood vessels 5 . Janus kinase (JAK) inhibitors, which prevent type I IFN signalling, suppressed the induction of IFN-inducible genes in T cells acquired from patients with SAVI 100 . Thus, such drugs may be useful for the treatment of patients with SAVI. It is tempting to consider whether mutations in TMEM173 or in genes encoding proteins that directly or indirectly regulate STING, such as cGAS, may contribute to other types of autoinflammatory diseases 102 . > Translocon-associated protein (TRAP). A complex of proteins that shunt proteins destined for N-linked glycosylation and secretion into the endoplasmic reticulum after translation.

[19] STING inhibitors target the cyclic dinucleotide binding pocket

• Authors: Ze Hong, Jiahao Mei, Chenhui Li, G. Bai, Munire Maimaiti et al.
• Year: 2021
• Venue: Proceedings of the National Academy of Sciences of the United States of America
• URL: https://www.semanticscholar.org/paper/e096ac00b789481474a0dc88c9f0ba7cc8583674
• DOI: 10.1073/pnas.2105465118
• PMID: 34099558
• PMCID: 8214703
• Citations: 214
• Influential citations: 10
• Summary: A specific STING inhibitor that binds to the STING CDN-binding pocket is a promising lead compound for STING-driven disease.
• Evidence snippets:
• Snippet 1 (score: 0.465) > pathway by aberrant self-DNAs leads to chronic IFN expression, which has been implicated in the development of some autoimmune disorders (25). Genetic mutations of genes that cause cytosolic accumulation of nucleic acids, including the DNase TREX1, RNASEH2A-C, SAMHD1, ADAR, and MDA5, cause a broad spectrum of inflammatory and autoimmune phenotypes, including Aicardi-Goutières syndrome (AGS), familial chilblain lupus, and systemic lupus erythematosus (SLE) (26)(27)(28). Trex1 deficiency in mice causes inflammatory myocarditis, progressive cardiomyopathy, and circulatory failure. Trex1-deficient mice lacking STING are completely protected from otherwise lethal inflammatory diseases, indicating the central role of STING in disease pathogenesis. Moreover, gain-of-function (GOF) mutations in STING cause early-onset vasculopathy and pulmonary inflammation in patients, known as STING-associated vasculopathy with onset in infancy (SAVI) (29,30). In addition, in some IFN or inflammation-driven disorders, including senescence, lethal sepsis, acute pancreatitis, Parkinson's Significance cGAS (cytosolic DNA sensor cyclic AMP-GMP synthase)-STING (stimulator of interferon genes) signaling is critical for sensing cytosolic DNA to initiate host immune responses against invading pathogens and cancer. However, inappropriate activation of STING signaling causes severe and often fatal autoimmune or autoinflammatory diseases. Hence, STING is an attractive drug target for the treatment of STING-driven autoimmune and inflammatory disorders. Therefore, there is a need to identify lead compounds that effectively inhibit human STING for further drug development. Here, we identified and characterized a STING-specific inhibitor SN-011 with high efficiency, specificity, and safety, paving the way for therapeutically manipulating STING-mediated clinical diseases. disease, nonalcoholic fatty liver disease, and chronic kidney fibrosis, blocking cGAS-STING signaling in mouse models ameliorates disease progression (24,(31)(32)(33)

[20] The role of cGAS-STING signaling in pulmonary fibrosis and its therapeutic potential

• Authors: Jing Zhang, Lanlan Zhang, Yutian Chen, Xiaobin Fang, Bo Li et al.
• Year: 2023
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/531f295bf1f7feccd535b4f7074d76f79fd8f9af
• DOI: 10.3389/fimmu.2023.1273248
• PMID: 37965345
• PMCID: 10642193
• Citations: 40
• Summary: This review aims to provide a comprehensive summary of the current knowledge regarding the role of cGAS-STING pathway in pulmonary fibrosis, and discusses the potential therapeutic implications of targeting the cGas- STING pathway, including the utilization of inhibitors ofcGAS and STING.
• Evidence snippets:
• Snippet 1 (score: 0.464) > This activation of the cGAS-STING innate immune pathway leads to the induction of type I interferon (IFN) gene expression (14). Type I interferons act in an autocrine manner, inducing expression of the STING gene. With increasing research into the cGAS-STING pathway, which is involved in autoimmunity, tumor immunity, cellular senescence, anti-viral and bacterial, this pathway may play a major role in the development of many disease (15)(16)(17)(18)(19). > Pirfenidone and nintedanib have been approved by the US Food and Drug Administration (FDA) for the treatment of pulmonary fibrosis (20). While these drugs have been shown to slow down the progression of the diseases, they are unable to reverse the disease. Lung transplantation, the last line of hope for patients, is not available to most patients due to its high cost and the risk of immune rejection (21). Research efforts are currently focused on investigating the molecular mechanisms that underlie the progression from acute lung inflammation to pulmonary fibrosis, as well as identifying new molecular pathways and therapeutic targets that can help prevent the development and progression of pulmonary fibrosis (4). Recent studies have highlighted the involvement of aberrant activation of cGAS-STING contributes to fibrotic lung diseases, such as sting-associated vasculopathy of infantile onset (SAVI), IPF, and silica-induced lung fibrosis (22,23). Mutations in STING lead to SAVI, an autoinflammatory syndrome in children characterized by interstitial lung disease (24). Alveolar macrophage-derived exosomes carrying Ficolin B activate the cGAS-STING pathway, exacerbating lung injury and fibrosis (25). Additionally, the induction of cellular senescence through damaged autologous DNA-mediated cGAS activation contributes to lung fibrosis, while targeting the cGAS-STING pathway can bypass cellular senescence and attenuate the fibrotic process (26,27). Furthermore, exposure to silica triggers cGAS-STING activation, resulting in lung inflammation and fibrosis (28)(29)(30).

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.