The commonTMEM173 HAQ, AQalleles rescue CD4 T cellpenia, restore T-regs, and preventSAVI (N153S)inflammatory disease in mice DOI Creative Commons
Alexandra Aybar-Torres,

Lennon A Saldarriaga,

Ann Pham

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 7, 2023

Abstract The significance of STING (encoded by the TMEM173 gene) in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human alleles R71H-G230A-R293Q ( HAQ) G230A-R293Q AQ ) are carried ∼60% East Asians ∼40% Africans, respectively. Here, we examine modulatory effects HAQ, on STING-associated vasculopathy with onset infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused gain-of-function mutations. CD4 T cellpenia is evident SAVI patients mouse models. Using knock-in mice expressing HAQ , Q293 found that splenocytes resist STING-mediated cell death ex vivo, establishing a critical role residue 293 death. HAQ/SAVI(N153S) AQ/SAVI(N153S) did not have cellpenia. HAQ/SAVI(N153S), more (∼10-fold, ∼20-fold, respectively) T-regs than WT/SAVI(N153S) mice. Remarkably, while they comparable TBK1, IRF3, NFκB activation as WT/SAVI AQ/SAVI no inflammation, regular body weight, normal lifespan. We propose promotes depleting cells vivo . Billions modern humans dominant alleles. research STING-targeting should consider heterogeneity humans. Teaser Common dominate SAVI(N154S) mutant

Language: Английский

Nucleic acid triggers of autoimmunity and autoinflammation DOI Creative Commons
Kaiyuan Hao, Ann Marshak‐Rothstein

Current Opinion in Immunology, Journal Year: 2025, Volume and Issue: 93, P. 102535 - 102535

Published: Jan. 30, 2025

Language: Английский

Citations

1
Author response: The common TMEM173 HAQ, AQ alleles rescue CD4 T cellpenia, restore T-regs, and prevent SAVI (N153S) inflammatory disease in mice DOI Open Access
Alexandra Aybar-Torres,

Lennon A Saldarriaga,

Ann Pham

et al.

Published: June 13, 2024

The significance of STING (encoded by the TMEM173 gene), in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human alleles R71H-G230A-R293Q (HAQ) G230A-R293Q (AQ) are carried ∼60% East Asians ∼40% Africans, respectively. Here, we examine modulatory effects HAQ, AQ on STING-associated vasculopathy with onset infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused gain-of-function mutations. CD4 T cellpenia is evident SAVI patients mouse models. Using knock-in mice expressing AQ, Q293, found that Q293 splenocytes resist STING-mediated cell death ex vivo, establishing a critical role residue 293 death. HAQ/SAVI(N153S) AQ/SAVI(N153S) did not have cellpenia. HAQ/SAVI(N153S), more (∼10-fold, ∼20-fold, respectively) T-regs than WT/SAVI(N153S) mice. Remarkably, while they comparable TBK1, IRF3, NFκB activation as WT/SAVI, AQ/SAVI no inflammation, regular body weight, normal lifespan. We propose promotes depleting cells vivo. Billions modern humans dominant alleles. research STING-targeting should consider heterogeneity humans.Teaser: One copy HAQ or gene prevents mutant-caused

Language: Английский

Citations

4
A novel STING variant triggers endothelial toxicity and SAVI disease DOI Creative Commons
Erika Valeri, Sara Breggion, Federica Barzaghi

et al.

The Journal of Experimental Medicine, Journal Year: 2024, Volume and Issue: 221(9)

Published: July 2, 2024

Gain-of-function mutations in STING cause STING-associated vasculopathy with onset infancy (SAVI) characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease. Here, we report characterize a novel variant (F269S) identified SAVI patient. Single-cell transcriptomics of patient bone marrow revealed spontaneous activation interferon (IFN) inflammatory pathways across cell types striking prevalence circulating naïve T cells was observed. Inducible F269S expression conferred enhanced signaling through ligand-independent translocation the protein to Golgi, protecting from viral infections but preventing their efficient immune priming. Additionally, endothelial promoted further exacerbated cytokine secretion cells, resulting inflammation damage. Our findings identify mutation as pathogenic causing SAVI, highlight importance crosstalk between context disease, contribute better understanding how aberrant can pathology.

Language: Английский

Citations

4
PARP7 inhibits type I interferon signaling to prevent autoimmunity and lung disease DOI Creative Commons
Devon Jeltema, Kay Knox, Nicole Dobbs

et al.

The Journal of Experimental Medicine, Journal Year: 2025, Volume and Issue: 222(5)

Published: Feb. 19, 2025

Type I IFN (IFN-I) induce hundreds of antiviral genes as well negative regulators that limit IFN-I signaling. Here, we investigate the family 16 PARPs and find 11 are ISGs, which 8 inhibit production. PARP7 is most potent feedback regulator Using Parp7−/− Parp7H532A/H532A mice, show loss leads to systemic autoimmunity characterized by splenomegaly increased autoantibodies inflammatory cytokines. also results in perivascular immune infiltration lung forms tertiary lymphoid structures. Mechanistically, inhibits multiple innate pathways a cell-intrinsic MARylation-dependent manner. interacts with IRF3 through catalytic domain disrupts IRF3:CBP/p300 transcriptional holocomplex required for Irf3−/− or Irf3S1/S1 (transcription defective) Sting−/− rescues mouse disease. Together, our study reveals physiological functions production maintains homeostasis particularly lung.

Language: Английский

Citations

0
The pathogenesis, clinical presentations and treatment of monogenic systemic vasculitis DOI
Ahmet Gül, Ivona Aksentijevich, Paul Brogan

et al.

Nature Reviews Rheumatology, Journal Year: 2025, Volume and Issue: unknown

Published: May 14, 2025

Language: Английский

Citations

0
STING deletion protects against amyloid β–induced Alzheimer's disease pathogenesis DOI Creative Commons
Jessica M. Thanos,

Olivia Campbell,

Maureen N. Cowan

et al.

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(5)

Published: May 1, 2025

Abstract INTRODUCTION While immune dysfunction has been increasingly linked to Alzheimer's disease (AD) progression, many major innate signaling molecules have yet be explored in AD pathogenesis using genetic targeting approaches. METHODS To investigate a role for the key adaptor molecule, stimulator of interferon genes (STING), AD, we deleted Sting1 5xFAD mouse model AD‐related amyloidosis and evaluated effects on pathology, neuroinflammation, gene expression, cognition. RESULTS Genetic ablation STING mice led improved control amyloid beta (Aβ) plaques, alterations microglial activation status, decreased levels neuritic dystrophy, protection against cognitive decline. Moreover, rescue neurological STING‐deficient was characterized by reduced expression type I both microglia excitatory neurons. DISCUSSION These findings reveal critical roles Aβ‐driven suggest that STING‐targeting therapeutics may offer promising strategies treat AD. Highlights Stimulator (STING) deficiency disease‐related results deposition altered status. Protection is associated with involved IFN signaling, neuronal health, oxidative stress. Loss leads spatial learning memory.

Language: Английский

Citations

0
DNA-sensing pathways in health, autoinflammatory and autoimmune diseases DOI
Mingqi Dong, Katherine A. Fitzgerald

Nature Immunology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 4, 2024

Language: Английский

Citations

2
The common TMEM173 HAQ, AQ alleles rescue CD4 T cellpenia, restore T-regs, and prevent SAVI (N153S) inflammatory disease in mice DOI Creative Commons
Alexandra Aybar-Torres,

Lennon A Saldarriaga,

Ann Pham

et al.

eLife, Journal Year: 2024, Volume and Issue: 13

Published: June 13, 2024

The significance of STING1 gene in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human alleles R71H-G230A-R293Q ( HAQ ) G230A-R293Q AQ are carried by ~60% East Asians ~40% Africans, respectively. Here, we examine the modulatory effects HAQ, on STING-associated vasculopathy with onset infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused gain-of-function mutations. CD4 T cellpenia is evident SAVI patients mouse models. Using Sting1 knock-in mice expressing , Q293 found that splenocytes resist STING1-mediated cell death ex vivo, establishing a critical role residue 293 death. HAQ/SAVI(N153S AQ/SAVI(N153S did not have cellpenia. HAQ/SAVI(N153S), more (~10-fold, ~20-fold, respectively) T-regs than WT/SAVI(N153S mice. Remarkably, while they comparable TBK1, IRF3, NFκB activation as WT/SAVI AQ/SAVI no inflammation, regular body weight, normal lifespan. We propose promotes depleting cells vivo. Billions modern humans dominant alleles. research STING1-targeting should consider heterogeneity humans.

Language: Английский

Citations

1
Single-cell RNA-sequencing of PBMCs from SAVI patients reveals disease-associated monocytes with elevated integrated stress response DOI Creative Commons
Camille de Cevins, Laure Delage, Maxime Batignes

et al.

Cell Reports Medicine, Journal Year: 2023, Volume and Issue: 4(12), P. 101333 - 101333

Published: Dec. 1, 2023

Gain-of-function mutations in stimulator of interferon gene 1 (STING1) result STING-associated vasculopathy with onset infancy (SAVI), a severe autoinflammatory disease. Although elevated type I (IFN) production is thought to be the leading cause symptoms observed patients, STING can induce set pathways, which have roles and severity SAVI remain elucidated. To this end, we performed multi-omics comparative analysis peripheral blood mononuclear cells (PBMCs) plasma from patients healthy controls, combined dataset PBMCs treated IFN-β. Our data reveal subset disease-associated monocyte, expressing CCL3, CCL4, IL-6, as well strong integrated stress response, suggest direct PERK activation by STING. Cell-to-cell communication inference indicates that these monocytes lead T cell early activation, resulting their senescence apoptosis. Last, propose transcriptomic signature independent IFN response.

Language: Английский

Citations

3
eLife assessment: The common TMEM173 HAQ, AQ alleles rescue CD4 T cellpenia, restore T-regs, and prevent SAVI (N153S) inflammatory disease in mice DOI Open Access
Carla V. Rothlin

Published: June 13, 2024

The significance of STING (encoded by the TMEM173 gene), in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human alleles R71H-G230A-R293Q (HAQ) G230A-R293Q (AQ) are carried ∼60% East Asians ∼40% Africans, respectively. Here, we examine modulatory effects HAQ, AQ on STING-associated vasculopathy with onset infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused gain-of-function mutations. CD4 T cellpenia is evident SAVI patients mouse models. Using knock-in mice expressing AQ, Q293, found that Q293 splenocytes resist STING-mediated cell death ex vivo, establishing a critical role residue 293 death. HAQ/SAVI(N153S) AQ/SAVI(N153S) did not have cellpenia. HAQ/SAVI(N153S), more (∼10-fold, ∼20-fold, respectively) T-regs than WT/SAVI(N153S) mice. Remarkably, while they comparable TBK1, IRF3, NFκB activation as WT/SAVI, AQ/SAVI no inflammation, regular body weight, normal lifespan. We propose promotes depleting cells vivo. Billions modern humans dominant alleles. research STING-targeting should consider heterogeneity humans.Teaser: One copy HAQ or gene prevents mutant-caused

Language: Английский

Citations

0