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  • 1
    Online Resource
    Online Resource
    Small Molecule IL-36γ Antagonist as a Novel Therapeutic Approach for Plaque Psoriasis
    Springer Science and Business Media LLC ; 2019
    In:  Scientific Reports Vol. 9, No. 1 ( 2019-06-24)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2019-06-24)
    Abstract: IL-36 cytokines are pro-inflammatory members of the IL-1 family that are upregulated in inflammatory disorders. Specifically, IL-36γ is highly expressed in active psoriatic lesions and can drive pro-inflammatory processes in 3D human skin equivalents supporting a role for this target in skin inflammation. Small molecule antagonists of interleukins have been historically challenging to generate. Nevertheless, we performed a small molecule high-throughput screen to identify IL-36 antagonists using a novel TR-FRET binding assay. Several compounds, including 2-oxypyrimidine containing structural analogs of the marketed endothelin receptor A antagonist Ambrisentan, were identified as hits from the screen. A-552 was identified as a the most potent antagonist of human IL-36γ, but not the closely related family member IL-36α, was capable of attenuating IL-36γ induced responses in mouse and human disease models. Additionally, x-ray crystallography studies identified key amino acid residues in the binding pocket present in human IL-36γ that are absent in human IL-36α. A-552 represents a first-in-class small molecule antagonist of IL-36 signaling that could be used as a chemical tool to further investigate the role of this pathway in inflammatory skin diseases such as psoriasis.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-019-45626-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2615211-3
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  • 2
    Online Resource
    Online Resource
    IL-23 induces regulatory T cell plasticity with implications for inflammatory skin diseases
    Springer Science and Business Media LLC ; 2019
    In:  Scientific Reports Vol. 9, No. 1 ( 2019-11-27)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2019-11-27)
    Abstract: Foxp3 + regulatory T cells (Tregs) represent a major fraction of skin resident T cells. Although normally protective, Tregs have been shown to produce pro-inflammatory cytokines in human diseases, including psoriasis. A significant hurdle in the Treg field has been the identification, or development, of model systems to study this Treg plasticity. To overcome this gap, we analyzed skin resident Tregs in a mouse model of IL-23 mediated psoriasiform dermatitis. Our results demonstrate that IL-23 drove the accumulation of Tregs; including a subpopulation that co-expressed RORγt and produced IL-17A. Genesis of this population was attenuated by a RORγt inverse agonist compound and clinically relevant therapeutics. In vitro , IL-23 drove the generation of CD4 + Foxp3 + RORγt + IL-17A + cells from Treg cells. Collectively, our data shows that IL-23 drives Treg plasticity by inducing a population of CD4 + Foxp3 + RORγt + IL-17A + cells that could play a role in the disease pathogenesis. Through this work, we define an in vitro system and a pre-clinical in vivo mouse model that can be used to further study Treg homeostasis and plasticity in the context of psoriasis.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-019-53240-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2615211-3
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  • 3
    Online Resource
    Online Resource
    Monocytes/Macrophages play a pathogenic role in IL-23 mediated psoriasis-like skin inflammation
    Springer Science and Business Media LLC ; 2019
    In:  Scientific Reports Vol. 9, No. 1 ( 2019-03-29)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2019-03-29)
    Abstract: Psoriasis is an immune-mediated inflammatory skin disease that affects millions worldwide. Studying immune cells involved in psoriasis pathogenesis is essential to identify effective and safe therapeutics for the disease. Using human psoriasis skin, activated macrophages were observed in both lesional and non-lesional skin, but were elevated in lesional skin. Activation of the IL-23/IL-17 pathway is integral to the development of psoriasis. To further characterize the monocyte/macrophage (Mon/Mac) population when the IL-23 pathway is activated, a murine model of intradermal injection of IL-23 was used. Flow cytometry revealed that Mon/Mac cells were the dominant immune population, particularly late in the model, highlighted by strong presence of Ly6C hi MHC II hi cells. The Mon/Mac cells were also shown to have high expression for TNFα but not IL-17A. Prophylactic dosing of a CSF-1R inhibitor to deplete Mon/Mac cells significantly reduced several inflammatory mediators from the skin tissue suggesting a pathogenic role for Mon/Mac. Treatment dosing of the inhibitor produced a less robust effect. Mon/Mac cells were also differentiated by levels of Ki67 and TNFα expression. These data point to an important contribution of Mon/Mac cells in IL-23 related skin inflammation and suggest that these cells are a significant player in the underlying pathophysiology of psoriasis.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-019-41655-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2615211-3
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  • 4
    Online Resource
    Online Resource
    IL ‐36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis
    Wiley ; 2019
    In:  Experimental Dermatology Vol. 28, No. 2 ( 2019-02), p. 113-120
    Details
    In: Experimental Dermatology, Wiley, Vol. 28, No. 2 ( 2019-02), p. 113-120
    Abstract: Psoriasis vulgaris ( PV ) results from activation of IL ‐23/Th17 immune pathway and is further amplified by cytokines/chemokines from skin cells. Among skin‐derived pro‐inflammatory cytokines, IL ‐36 family members are highly upregulated in PV patients and play a critical role in general pustular psoriasis. However, there is limited data showing crosstalk between the IL ‐23 and IL ‐36 pathways in PV . Herein, potential attenuation of skin inflammation in the IL ‐23‐induced mouse model of psoriasiform dermatitis by functional inhibition of IL ‐36 receptor ( IL ‐36R) was interrogated. Anti‐mouse IL ‐36R monoclonal antibodies ( mA bs) were generated and validated in vitro by inhibiting IL ‐36α‐induced secretion of CXCL 1 from NIH 3T3 cells. Antibody target engagement was demonstrated by inhibition of CXCL 1 production in a novel acute model of IL ‐36α systemic injection in mice. In addition, anti‐ IL ‐36R mA bs inhibited tissue inflammation and inflammatory gene expression in an IL ‐36α ear injection model of psoriasiform dermatitis demonstrating engagement of the target in the ear skin. To elucidate the possible role of IL ‐36 signalling in IL ‐23/Th17 pathway, the ability of anti‐ IL ‐36R mA bs to inhibit skin inflammation in an IL ‐23 ear injection model was assessed. Inhibiting the IL ‐36 pathway resulted in significant attenuation of skin thickening and psoriasis‐relevant gene expression. Taken together, these data suggest a role for IL ‐36 signalling in the IL ‐23/Th17 signalling axis in PV.
    Type of Medium: Online Resource
    ISSN: 0906-6705 , 1600-0625
    URL: Issue
    URL: Article
    DOI: 10.1111/exd.2019.28.issue-2
    DOI: 10.1111/exd.13841
    RVK:
    XA 42446
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2026228-0
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  • 5
    Online Resource
    Online Resource
    Importance of PLD2 in an IL ‐23 driven psoriasiform dermatitis model and potential link to human psoriasis
    Wiley ; 2023
    In:  The Journal of Dermatology Vol. 50, No. 10 ( 2023-10), p. 1321-1329
    Details
    In: The Journal of Dermatology, Wiley, Vol. 50, No. 10 ( 2023-10), p. 1321-1329
    Abstract: Phospholipase D2 (PLD2), a major isoform of the PLD family, has been reported to regulate inflammatory responses. Thus far, the relevance of PLD2 in psoriasis, an inflammatory skin disease, has not been explored. In the current study, we examined PLD2 expression in the skin of psoriasis patients and the role of PLD2 in an interleukin (IL)‐23‐induced mouse model of psoriasiform dermatitis. Both in situ hybridization and bulk RNA sequencing showed PLD2 gene expression is significantly higher in lesional relative to non‐lesional skin of psoriasis patients or the skin of healthy subjects. PLD2 expression is also enriched in residual lesions from patients on biologic therapies. Murine in vivo studies showed that PLD2 deficiency significantly reduced psoriasiform inflammation in IL‐23‐injected ears, as reflected by decreases in ear thickness, expression of defensin beta 4A and the S100 calcium binding protein A7A, macrophage infiltrate, and expression of CXCL10 and IL‐6. However, the expression of type 17 cytokines, IL‐17A and IL‐17F, were not reduced. Dual knockout of PLD1 and PLD2 offered little additional protection compared to PLD2 knockout alone in the IL‐23 model. In addition, pharmacological inhibition with a pan‐PLD1/PLD2 inhibitor also suppressed IL‐23‐induced psoriasiform dermatitis. Bone‐marrow‐derived macrophages from wild type (WT) and PLD2 knockout (KO) mice exhibited little difference in viability and sensitivity to lipopolysaccharide and/or interferon gamma, or resiquimod (R848). PLD2 deficiency did not alter the differentiation and function of Th17 cells in an ex vivo study with splenocytes isolated from WT and PLD2 KO mice. Overall, these data suggest that PLD2 may play a role in the pathophysiology of psoriasis. Reducing macrophage infiltrate and cytokine/chemokine production might contribute to an anti‐inflammatory effect observed in PLD2 knockout mice. Further studies are required to better understand the mechanisms by which PLD2 contributes to skin lesions in psoriasis patients and psoriasiform dermatitis models.
    Type of Medium: Online Resource
    ISSN: 0385-2407 , 1346-8138
    URL: Issue
    URL: Article
    DOI: 10.1111/jde.v50.10
    DOI: 10.1111/1346-8138.16899
    RVK:
    XA 53120
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2222121-9
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