STAT3 serine phosphorylation is required for TLR4 metabolic reprogramming and IL-1β expression

Balic, Jesse J.; Albargy, Hassan; Luu, Kevin; Kirby, Francis J.; Jayasekara, W. Samantha N.; Mansell, Finbar; Garama, Daniel J.; Nardo, Dominic De; Baschuk, Nikola; Louis, Cynthia; Humphries, Fiachra; Fitzgerald, Katherine A.; Latz, Eicke; Gough, Daniel J.; Mansell, Ashley

doi:10.1038/s41467-020-17669-5

Cited by 111 publications

(94 citation statements)

References 37 publications

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“…Nucleic-acid-sensing TLRs are mainly expressed in the endosomes ( 93 ) and comprise TLR3 [recognizes dsRNA ( 94 )], TLR7 and TLR8 [recognize ssRNA ( 95 )] and TLR9 [recognizes unmethylated CpG-containing DNA motifs ( 96 )]. Activation of these TLRs, with the exception of TLR3, incorporates MyD88 to the respective receptor complex which subsequently interacts with TRAF6 leading to nuclear translocation of NFkB ( 97 ) and type-I IFN induction ( 98 ). TLR3 alternatively signals via the adaptor TRIF which activates TBK1 and subsequently leads to type-I IFN induction via phosphorylation of IRF3 ( 97 ).…”

Section: Interface Dermatitis—the Pathogenic Backgroundmentioning

confidence: 99%

“…Activation of these TLRs, with the exception of TLR3, incorporates MyD88 to the respective receptor complex which subsequently interacts with TRAF6 leading to nuclear translocation of NFkB ( 97 ) and type-I IFN induction ( 98 ). TLR3 alternatively signals via the adaptor TRIF which activates TBK1 and subsequently leads to type-I IFN induction via phosphorylation of IRF3 ( 97 ). Furthermore, TLR3 signaling can activate cell death cascades by engaging RIP1 and RIP3 ( 99 ).…”

Section: Interface Dermatitis—the Pathogenic Backgroundmentioning

confidence: 99%

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Immunostimulatory Endogenous Nucleic Acids Perpetuate Interface Dermatitis—Translation of Pathogenic Fundamentals Into an In Vitro Model

et al. 2021

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Interface dermatitis is a histopathological pattern mirroring a distinct cytotoxic immune response shared by a number of clinically diverse inflammatory skin diseases amongst which lichen planus and cutaneous lupus erythematosus are considered prototypic. Interface dermatitis is characterized by pronounced cytotoxic immune cell infiltration and necroptotic keratinocytes at the dermoepidermal junction. The initial inflammatory reaction is established by cytotoxic immune cells that express CXC chemokine receptor 3 and lesional keratinocytes that produce corresponding ligands, CXC motif ligands 9/10/11, recruiting the effector cells to the site of inflammation. During the resulting anti-epithelial attack, endogenous immune complexes and nucleic acids are released from perishing keratinocytes, which are then perceived by the innate immune system as danger signals. Keratinocytes express a distinct signature of pattern recognition receptors and binding of endogenous nucleic acid motifs to these receptors results in interferon-mediated immune responses and further enhancement of CXC chemokine receptor 3 ligand production. In this perspective article, we will discuss the role of innate nucleic acid sensing as a common mechanism in the perpetuation of clinically heterogeneous diseases featuring interface dermatitis based on own data and a review of the literature. Furthermore, we will introduce a keratinocyte-specific in vitro model of interface dermatitis as follows: Stimulation of human keratinocytes with endogenous nucleic acids alone and in combination with interferon gamma leads to pronounced production of distinct cytokines, which are essential in the pathogenesis of interface dermatitis. This experimental approach bears the capability to investigate potential therapeutics in this group of diseases with unmet medical need.

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Section: Interface Dermatitis—the Pathogenic Backgroundmentioning

confidence: 99%

Section: Interface Dermatitis—the Pathogenic Backgroundmentioning

confidence: 99%

Immunostimulatory Endogenous Nucleic Acids Perpetuate Interface Dermatitis—Translation of Pathogenic Fundamentals Into an In Vitro Model

et al. 2021

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“…In this article, we discuss a new study from the laboratory of Ashley Mansell that successfully links innate immune receptor signaling to metabolic changes in macrophages, establishing for the first time an uninterrupted pathway from ligand binding to mitochondrial reprogramming and subsequential effector function modulation in this cell type 1 …”

Section: Figurementioning

confidence: 99%

Bridging the gap – a new role for STAT3 in TLR4‐mediated metabolic reprogramming

Weiss

O’Neill

2020

Immunol. Cell Biol.

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“…Kagoya et al have modified a CAR construct to activate specifically STAT3 [ 76 ], a transcription factor involved in the rapid innate immune mitochondria reprogramming and inflammatory response upon antigen stimulation [ 77 ]. The modified CAR construct contained a truncated domain of the Il2 receptor and a STAT3 binding tyrosine motif (YXXQ), as well as the co-stimulatory domain CD28.…”

Section: Armoring Car T-cells: Improving the Intrinsic Anti-tumormentioning

confidence: 99%

Manipulating the Metabolism to Improve the Efficacy of CAR T-Cell Immunotherapy

Pellegrino

Bufalo

Angelis

et al. 2020

Cells

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The adoptive transfer of the chimeric antigen receptor (CAR) expressing T-cells has produced unprecedented successful results in the treatment of B-cell malignancies. However, the use of this technology in other malignancies remains less effective. In the setting of solid neoplasms, CAR T-cell metabolic fitness needs to be optimal to reach the tumor and execute their cytolytic function in an environment often hostile. It is now well established that both tumor and T cell metabolisms play critical roles in controlling the immune response by conditioning the tumor microenvironment and the fate and activity of the T cells. In this review, after a brief description of the tumoral and T cell metabolic reprogramming, we summarize the latest advances and new strategies that have been developed to improve the metabolic fitness and efficacy of CAR T-cell products.

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STAT3 serine phosphorylation is required for TLR4 metabolic reprogramming and IL-1β expression

Cited by 111 publications

References 37 publications

Immunostimulatory Endogenous Nucleic Acids Perpetuate Interface Dermatitis—Translation of Pathogenic Fundamentals Into an In Vitro Model

Immunostimulatory Endogenous Nucleic Acids Perpetuate Interface Dermatitis—Translation of Pathogenic Fundamentals Into an In Vitro Model

Bridging the gap – a new role for STAT3 in TLR4‐mediated metabolic reprogramming

Manipulating the Metabolism to Improve the Efficacy of CAR T-Cell Immunotherapy

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