Endothelial STING controls Tcell transmigration in an IFN-I dependent manner

Anastasiou, Marina; Newton, Gail; Kaur, Kuljeet; Carrillo‐Salinas, Francisco; Smolgovsky, Sasha; Bayer, Abraham L; Ilyukha, Vladimir; Sharma, Satendra; Poltorak, Alexander; Luscinskas, Francis W.; Alcaide, Pilar

doi:10.1172/jci.insight.149346

Cited by 26 publications

(24 citation statements)

References 49 publications

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“…The pro-inflammatory cytokine TNF-α, which can be released by pro-inflammatory macrophages, was also similarly increased in the hearts of WT and CD43−/− mice in response to cardiac pressure overload, compared to Sham controls, suggesting that CD43 does not contribute to cardiac TNF-α expression in experimental HF ( Figure 4E ). A characteristic of pro-inflammatory cardiac infiltrating myeloid cells is the production of the chemokine CXCL10, which is a potent chemoattractant for Th1 cells and is mainly secreted by immune cells ( Ngwenyama et al, 2019 ; Anastasiou et al, 2021 ). Given the striking decrease of CD4+ T cells in the CD43−/− TAC hearts, we next investigated cardiac CXCL10 expression.…”

Section: Resultsmentioning

confidence: 99%

Sialomucin CD43 Plays a Deleterious Role in the Development of Experimental Heart Failure Induced by Pressure Overload by Modulating Cardiac Inflammation and Fibrosis

et al. 2021

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Sialomucin CD43 is a transmembrane protein differentially expressed in leukocytes that include innate and adaptive immune cells. Among a variety of cellular processes, CD43 participates in T cell adhesion to vascular endothelial cells and contributes to the progression of experimental autoimmunity. Sequential infiltration of myeloid cells and T cells in the heart is a hallmark of cardiac inflammation and heart failure (HF). Here, we report that CD43−/− mice have improved survival to HF induced by transverse aortic constriction (TAC). This enhanced survival is associated with improved systolic function, decreased cardiac fibrosis, and significantly reduced T cell cardiac infiltration in response to TAC compared to control wild-type (WT) mice. Lack of CD43 did not alter the number of myeloid cells in the heart, but resulted in decreased cardiac CXCL10 expression, a chemoattractant for T cells, and in a monocyte shift to anti-inflammatory macrophages in vitro. Collectively, these findings unveil a novel role for CD43 in adverse cardiac remodeling in pressure overload induced HF through modulation of cardiac T cell inflammation.

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Section: Resultsmentioning

confidence: 99%

Sialomucin CD43 Plays a Deleterious Role in the Development of Experimental Heart Failure Induced by Pressure Overload by Modulating Cardiac Inflammation and Fibrosis

et al. 2021

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“…As a representative example, the bronchial circulation (which arises from the aorta and intercostal arteries with high pressure) supplies a small proportion of the pulmonary tissue in mice compared to humans. These differences seem of importance when studying SAVI, where the vascular phenotype is predominant and endothelial cells may be a key player of lung disease [69]. Secondly, STING protein differs between humans and mice [70].…”

Section: Futures Perspectives To Decipher Savi Lung Disease Pathogenesismentioning

confidence: 99%

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

David

Frémond

2022

Cells

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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.

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“…Tumor blood vessels appear disorganized and immature, which reduces chemotaxis of immune cells into TME but increases the distant metastasis of tumor cells. A recent study proposed that T-cell transendothelial migration was regulated by endothelial STING in an IFN-I-dependent manner ( Anastasiou et al, 2021 ). IFN-β was proposed to downregulate VEGF expression and suppress tumor angiogenesis ( Takano et al, 2014 ), but it was also shown that IFN-α and IFN-β promoted vasculogenic mimicry formation and facilitated tumor growth ( Jablonska et al, 2010 ; Yeh et al, 2018 ).…”

Section: Remodeling Of Tme Induced By Dna Damage Through the Cgas/sti...mentioning

confidence: 99%

DNA Damage and Activation of cGAS/STING Pathway Induce Tumor Microenvironment Remodeling

Shen

Liu

Wang

et al. 2022

Front. Cell Dev. Biol.

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DNA damage occurs throughout tumorigenesis and development. The immunogenicity of DNA makes it an immune stimulatory molecule that initiates strong inflammatory responses. The cGAS/STING pathway has been investigated as a critical receptor in both exogenous and endogenous DNA sensing to activate the innate immune response. Growing lines of evidence have indicated that activation of the cGAS/STING pathway is critical in antitumor immunity. Recent studies have demonstrated the outstanding advancement of this pathway in tumor-combined immunotherapy; accordingly, increased studies focus on exploration of STING pathway agonists and analogues. However, current studies propose the potential use of the cGAS/STING pathway in tumor initiation and metastasis. Here, we review the molecular mechanisms and activation of the cGAS/STING pathway, and the relationship between DNA damage and this pathway, particularly highlighting the remodeling of immune contexture in tumor environment (TME) triggered by cascade inflammatory signals. A detailed understanding of TME reprogramming initiated by this pathway may pave the way for the development of new therapeutic strategies and rational clinical application.

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Endothelial STING controls Tcell transmigration in an IFN-I dependent manner

Cited by 26 publications

References 49 publications

Sialomucin CD43 Plays a Deleterious Role in the Development of Experimental Heart Failure Induced by Pressure Overload by Modulating Cardiac Inflammation and Fibrosis

Sialomucin CD43 Plays a Deleterious Role in the Development of Experimental Heart Failure Induced by Pressure Overload by Modulating Cardiac Inflammation and Fibrosis

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

DNA Damage and Activation of cGAS/STING Pathway Induce Tumor Microenvironment Remodeling

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