Constitutively Active STING Triggers Inflammation via Enhanced TNF Signaling in a Mouse Model of STING-Associated Vasculopathy

Kernekoncepter

Constitutive activation of STING, a key regulator of innate immunity, leads to the manifestation of the autoinflammatory disease STING-associated vasculopathy with onset in infancy (SAVI). This study demonstrates that aberrant tumor necrosis factor (TNF) signaling through TNFR1 and TNFR2 plays a pivotal role in the pathogenesis of SAVI in a mouse model.

Resumé

The study investigates the role of TNF signaling in the pathogenesis of SAVI, a severe autoinflammatory disease caused by constitutive activation of the innate immune receptor STING.
Key findings:

Pharmacological inhibition of TNF signaling using Infliximab partially rescued the T cell lymphopenia in STING ki mice, a mouse model of SAVI, but had no effect on the interstitial lung disease.
Genetic inactivation of TNFR1 and TNFR2 in STING ki mice rescued the loss of thymocytes, reduced interstitial lung disease, and neurodegeneration.
Lack of TNFR1/2 signaling blunted the transcription of cytokines, chemokines, and adhesion proteins in STING ki mice, which are induced by chronic STING activation.
Endothelial cells from STING ki mice showed increased expression of inflammatory mediators and adhesion factors in a TNFR-dependent manner, leading to enhanced neutrophil attachment and transendothelial migration.
The study highlights the pivotal role of TNF signaling, particularly through TNFR1, in the pathogenesis of SAVI and suggests that TNF blockade could be a valuable therapeutic option for SAVI patients.

Statistik

STING ki mice showed a profound decrease in the numbers of CD4+ and CD8+ T cells in peripheral blood compared to STING WT mice.
Infliximab treatment significantly increased the numbers of blood CD8+ T cells in STING ki mice.
Genetic inactivation of TNFR1 and TNFR2 in STING ki mice resulted in a significant increase in the numbers of thymic single positive CD4+ and CD8+ T cells.
Lack of TNFR1/2 signaling completely rescued the inflammatory transcriptional signature in the lungs of STING ki mice.
Inactivation of TNFR1 alone or TNFR1/2 together almost completely prevented the development of interstitial lung disease in STING ki mice.
Endothelial cells from STING ki mice showed increased expression of inflammatory cytokines, chemokines, and adhesion factors in a TNFR-dependent manner.

Citater

"Constitutive activation of STING by gain-of-function mutations triggers manifestation of the systemic autoinflammatory disease STING-associated vasculopathy with onset in infancy (SAVI)."
"Genetic inactivation of TNFR1 and TNFR2 rescued the loss of thymocytes, reduced interstitial lung disease and neurodegeneration."
"Lack of TNFR1/2 signaling reverts the inflammatory state of primary lung endothelial cells in STING ki mice, including their transcriptional transmigration signature."

Vigtigste indsigter udtrukket fra

Tissue inflammation induced by constitutively active STING is mediated by enhanced TNF signaling

by Luks... kl. www.biorxiv.org 04-29-2024

https://www.biorxiv.org/content/10.1101/2024.04.25.591149v1

Dybere Forespørgsler

What other signaling pathways, besides TNF, might be involved in the pathogenesis of SAVI, and how could they be targeted therapeutically?

SAVI is a complex autoinflammatory disease characterized by constitutive activation of the STING pathway, leading to uncontrolled inflammation. Besides TNF signaling, other pathways such as NF-κB, type I interferon (IFN I), and chemokine signaling are also implicated in the pathogenesis of SAVI. Targeting these pathways therapeutically could involve the use of specific inhibitors or antagonists to modulate the aberrant immune response. For example, inhibitors of NF-κB signaling, such as IKK inhibitors, could be explored to dampen the inflammatory cascade in SAVI. Additionally, targeting the type I IFN pathway with IFNAR antagonists or JAK inhibitors may help in reducing the excessive interferon response seen in SAVI.

How do the distinct roles of TNFR1 and TNFR2 in the regulation of inflammation and cellular homeostasis contribute to the complex pathology of SAVI?

TNFR1 and TNFR2 play distinct roles in the regulation of inflammation and cellular homeostasis. TNFR1 is primarily involved in proinflammatory responses within the innate immune system, while TNFR2 is associated with cellular homeostasis and anti-inflammatory responses. In the context of SAVI, the dysregulation of TNFR1 signaling leads to the overproduction of inflammatory cytokines and chemokines, contributing to the systemic autoinflammatory symptoms observed in SAVI. On the other hand, the protective role of TNFR2 in cellular homeostasis may help in mitigating the inflammatory response to some extent. The imbalance between TNFR1 and TNFR2 signaling in SAVI results in a dysregulated immune response and contributes to the complex pathology of the disease.

Given the involvement of endothelial dysfunction in SAVI, could therapies targeting endothelial barrier integrity and function provide additional benefits for SAVI patients?

Therapies targeting endothelial barrier integrity and function could offer additional benefits for SAVI patients by addressing the underlying vascular dysfunction associated with the disease. Since endothelial dysfunction plays a crucial role in the pathogenesis of SAVI, interventions aimed at preserving endothelial barrier function and reducing inflammation in the vasculature could help in alleviating symptoms and improving outcomes for patients. Strategies such as endothelial cell-targeted therapies, anti-inflammatory agents, and agents promoting vascular health could be explored to enhance endothelial barrier integrity and function in SAVI. By restoring vascular homeostasis and reducing inflammation in the endothelium, these therapies may provide added benefits in managing the complex pathology of SAVI.