STING Mediates Lupus via the Activation of Conventional Dendritic Cell Maturation and Plasmacytoid Dendritic Cell Differentiation

Thim-Uam, Arthid; Prabakaran, Thaneas; Tansakul, Mookmanee; Makjaroen, Jiradej; Wongkongkathep, Piriya; Chantaravisoot, Naphat; Saethang, Thammakorn; Leelahavanichkul, Asada; Benjachat, Thitima; Paludan, Søren R.; Pisitkun, Trairak; Pisitkun, Prapaporn

doi:10.1016/j.isci.2020.101530

Cited by 52 publications

(54 citation statements)

References 65 publications

(82 reference statements)

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“…BCAP is a major modulator of TLR signaling, downregulating NF-kB activation [ 36 ] and favoring type I IFN induction [ 21 ]. Very recent data showed that activation of the STING-Lyn pathway leads to PIK3AP1 hyper-expression, which can be relevant to the development of SLE in lupus prone mice, thus adding substance to our findings [ 37 ]. The BCAP impact on the transition of macrophages from a “proinflammatory state” to a “reparative state” could influence the development of IFN-producing macrophages and autoimmune B cells [ 38 ].…”

Section: Discussionsupporting

confidence: 76%

Priming of the cGAS-STING-TBK1 Pathway Enhances LPS-Induced Release of Type I Interferons

Tesser

Piperno

et al. 2021

Cells

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Cytoplasmic nucleic acids sensing through cGAS-STING-TBK1 pathway is crucial for the production of antiviral interferons (IFNs). IFN production can also be induced by lipopolysaccharide (LPS) stimulation through Toll-like receptor 4 (TLR4) in appropriate conditions. Of note, both IFN production and dysregulated LPS-response could play a role in the pathogenesis of Systemic Lupus Erythematosus (SLE). Indeed, LPS can trigger SLE in lupus-prone mice and bacterial infections can induce disease flares in human SLE. However, the interactions between cGAS and TLR4 pathways to IFNs have been poorly investigated. To address this issue, we studied LPS-stimulation in cellular models with a primed cGAS-STING-TBK1 pathway. cGAS-stimulation was naturally sustained by undigested self-nucleic acids in fibroblasts from DNase2-deficiency interferonopathy, whilst it was pharmacologically obtained by cGAMP-stimulation in THP1 cells and murine bone marrow-derived dendritic cells. We showed that cells with a primed cGAS-STING-TBK1 pathway displayed enhanced IFNs production after TLR4-challenge. STING-inhibition did not affect IFN production after LPS alone, but prevented the amplified IFN production in cGAMP-primed cells, suggesting that functional STING is required for priming-dependent enhancement. Furthermore, we speculated that an increased PIK3AP1 expression in DNase2-deficient fibroblasts may link cGAMP-priming with increased LPS-induced IFN production. We showed that both the hyper-expression of PIK3API and the enhanced LPS-induced IFN production can be contrasted by STING inhibitors. Our results may explain how bacterial LPS can synergize with cGAS-pathway in promoting the development of SLE-like autoimmunity.

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Section: Discussionsupporting

confidence: 76%

Priming of the cGAS-STING-TBK1 Pathway Enhances LPS-Induced Release of Type I Interferons

Tesser

Piperno

et al. 2021

Cells

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“…Early work found that the genetic deletion of STING in the lupus-prone MRL.Fas lpr mice aggravated the disease phenotype 139 . By contrast, in another model driven by a deletion in the lupus susceptibility gene Fcgr2b , Sting1 null mice were protected from development of various disease manifestations, including elevated autoantibody titres and glomerulonephritis, and showed improved overall survival 140 . Moreover, cGAS–STING plays a pathogenic role in a variety of distinct models that promote lupus-like symptoms through a range of mechanisms.…”

Section: Activation Of Cgas–sting In Disease Contextsmentioning

confidence: 82%

“…Pathology due to defects in a subset of AGS genes is rescued in cGAS-deficient or STING-deficient mice 125 – 127 , 192 – 194 Familial chilblain lupus Disease can be caused by STING1 GOF mutation 195 COPA syndrome Pathology reduced in STING-deficient mice or mice treated with a STING inhibitor and in patient cells upon STING suppression 37 , 38 , 133 , 134 Autoimmune diseases Systemic lupus erythematosus Subset of patients have elevated cGAMP levels. Pathology of certain mouse models, which display a lupus-like phenotype, can be rescued in STING-deficient mice 135 , 136 , 140 Rheumatoid arthritis Reduced cytokine expression in patient cells following cGAS or STING knockdown 196 Neurological disorders Ischaemic brain injury Pathology reduced in mouse models treated with inhibitory oligonucleotide A151 197 Parkinson disease Pathology reduced in STING-deficient mouse models 91 General neurodegeneration Reduced inflammation markers seen in a STING-deficient mouse model 148 Huntington disease Cytokine expression within patient cells reduced upon cGAS depletion 147 Amyotrophic lateral sclerosis and frontotemporal dementia Protection in STING-deficient mice or in mice treated with a STING inhibitor. Reduced type I interferon expression in patient cells treated with a STING or cGAS inhibitor 101 , 145 Age-dependent macular degeneration Protection in cGAS-deficient and STING-deficient mouse models 198 Traumatic brain injury Reduced neuroinflammation seen in STING-deficient mice 207 Met...…”

Section: Activation Of Cgas–sting In Disease Contextsmentioning

confidence: 99%

The cGAS–STING pathway as a therapeutic target in inflammatory diseases

et al. 2021

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The cGAS–STING signalling pathway has emerged as a key mediator of inflammation in the settings of infection, cellular stress and tissue damage. Underlying this broad involvement of the cGAS–STING pathway is its capacity to sense and regulate the cellular response towards microbial and host-derived DNAs, which serve as ubiquitous danger-associated molecules. Insights into the structural and molecular biology of the cGAS–STING pathway have enabled the development of selective small-molecule inhibitors with the potential to target the cGAS–STING axis in a number of inflammatory diseases in humans. Here, we outline the principal elements of the cGAS–STING signalling cascade and discuss the general mechanisms underlying the association of cGAS–STING activity with various autoinflammatory, autoimmune and degenerative diseases. Finally, we outline the chemical nature of recently developed cGAS and STING antagonists and summarize their potential clinical applications.

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“…STING was recenlty implicated in the autoimmune phenotypes that develop in FcγR2-/- mice on a 129 background. However, since these mice were intercrossed with B6 STING gt mice, the potential contribution of 129-associated risk alleles linked to the STING locus need to be considered ( 18 ). cGAMP, the cyclic dinucleotide generated by cGAS that activates STING, has been shown to be modestly elevated in the serum of a limited number of SLE patients ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE

et al. 2021

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Detection of DNA is an important determinant of host-defense but also a driver of autoinflammatory and autoimmune diseases. Failure to degrade self-DNA in DNAseII or III(TREX1)-deficient mice results in activation of the cGAS-STING pathway. Deficiency of cGAS or STING in these models ameliorates disease manifestations. However, the contribution of the cGAS-STING pathway, relative to endosomal TLRs, in systemic lupus erythematosus (SLE) is controversial. In fact, STING deficiency failed to rescue, and actually exacerbated, disease manifestations in Fas-deficient SLE-prone mice. We have now extended these observations to a chronic model of SLE induced by the i.p. injection of TMPD (pristane). We found that both cGAS- and STING-deficiency not only failed to rescue mice from TMPD-induced SLE, but resulted in increased autoantibody production and higher proteinuria levels compared to cGAS STING sufficient mice. Further, we generated cGASKOFaslpr mice on a pure MRL/Faslpr background using Crispr/Cas9 and found slightly exacerbated, and not attenuated, disease. We hypothesized that the cGAS-STING pathway constrains TLR activation, and thereby limits autoimmune manifestations in these two models. Consistent with this premise, mice lacking cGAS and Unc93B1 or STING and Unc93B1 developed minimal systemic autoimmunity as compared to cGAS or STING single knock out animals. Nevertheless, TMPD-driven lupus in B6 mice was abrogated upon AAV-delivery of DNAse I, implicating a DNA trigger. Overall, this study demonstrated that the cGAS-STING pathway does not promote systemic autoimmunity in murine models of SLE. These data have important implications for cGAS-STING-directed therapies being developed for the treatment of systemic autoimmunity.

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STING Mediates Lupus via the Activation of Conventional Dendritic Cell Maturation and Plasmacytoid Dendritic Cell Differentiation

Cited by 52 publications

References 65 publications

Priming of the cGAS-STING-TBK1 Pathway Enhances LPS-Induced Release of Type I Interferons

Priming of the cGAS-STING-TBK1 Pathway Enhances LPS-Induced Release of Type I Interferons

The cGAS–STING pathway as a therapeutic target in inflammatory diseases

cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE

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