Mechanistic and pharmacological assessment of murine IL-23 mediated psoriasiform dermatitis; implications for drug discovery

Gauld, Stephen B.; Gauvin, Donna M.; Olson, L.; Leys, Laura; Paulsboe, Stephanie; Liu, Zheng; Edelmayer, Rebecca M.; Wetter, J.; Salte, K.; Wang, Yibing; Huang, Susan M.; Honoré, Prisca; McGaraughty, S.

doi:10.1016/j.jdermsci.2018.08.001

Cited by 14 publications

(40 citation statements)

References 33 publications

(40 reference statements)

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“…Direct intradermal injection of IL‐36α into mouse ears produced a robust inflammatory response as evidenced by ear swelling, epidermal thickening/keratinocyte proliferation, macrophage accumulation, immune cell accumulation/proliferation (also in DLN) and increased expression of IL‐17A, IL‐6, IL‐22, CXCL1, S100a7a and Defb4, which are genes/pathways associated with psoriatic inflammation . The increased expression of IL‐17A and IL‐22 supports previous findings that IL‐36 cytokines potentiate the production of Th17 cytokines contributing to the cytokine network in psoriasis .…”

Section: Discussionsupporting

confidence: 84%

“…Recently, it was reported that direct intradermal injection of IL‐36 cytokines (combination of α, β and γ) into mouse ear skin produced ear swelling as observed in the current study. The major component of inflammatory infiltration from our observations was also myeloid cells, specifically macrophages, which is similar to that in the IL‐23 model . Overall, the inflammatory phenotype of the IL‐36α ear injection model recapitulated key features of psoriatic skin lesions .…”

Section: Discussionsupporting

confidence: 65%

“…Cytokine (IL‐23 or IL‐36α) was injected (in 20 μL) intradermally to the ears of C56BL/6 mice using 30 gauge needles under light anaesthesia . Recombinant mouse IL‐23 and truncated IL‐36α (R&D systems, Minneapolis, MN, USA) were prepared in PBS/0.1%BSA at 1 μg/20 μL and 0.2 μg/20 μL, respectively.…”

Section: Methodsmentioning

confidence: 99%

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IL‐36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis

Paulsboe

Wetter

et al. 2018

Experimental Dermatology

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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 (mAbs) were generated and validated in vitro by inhibiting IL‐36α‐induced secretion of CXCL1 from NIH 3T3 cells. Antibody target engagement was demonstrated by inhibition of CXCL1 production in a novel acute model of IL‐36α systemic injection in mice. In addition, anti‐IL‐36R mAbs 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 mAbs 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.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 65%

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IL‐36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis

Paulsboe

Wetter

et al. 2018

Experimental Dermatology

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“…As expected, prophylactic dosing (starting at day 0, prior to the injection of the MC and onset of disease) of the anti‐IL‐23p40 completely prevented MC‐induced increases in ear thickness, dermal and epidermal area, and gene expression. Interestingly, these data differ from the same anti‐IL‐23p40 antibody tested by our group prophylactically in the IL‐23 ear injection model, in which the same dose only achieved approximately 50% inhibition of several endpoints . As noted in this paper, the decreased efficacy in the ear injection model may be driven by an IL‐23‐independent component (e.g.…”

Section: Discussioncontrasting

confidence: 71%

“…Repeated intradermal injection of IL‐23 to mice has been used as a mechanistic model that recapitulates many key features of psoriasis . These models have been useful in understanding skin inflammation associated with activation of this pathway and evaluating novel therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Characterization of psoriasiform dermatitis induced by systemic injection of interleukin‐23 minicircles in mice

Leys

Wang

Paulsboe

et al. 2019

The Journal of Dermatology

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The interleukin (IL)‐23/IL‐17 axis plays a central role in the pathogenesis of psoriasis and is elevated in lesional psoriatic skin. Different murine models have been developed to mimic this pathophysiology each carrying specific merits and limitations. In an attempt to address some of these limitations, B10.RIII mice received a single hydrodynamic injection of IL‐23 minicircles (MC) to induce hepatic transcription and the endogenous production of IL‐23. Plasma and ear IL‐23 levels were dose‐dependently (0.3–3 μg) increased in MC injected mice and were sustained over the 14‐day study duration. Beginning on day 7 post‐injection, mice developed dose‐related ear inflammation, histologically confirmed increases in epidermal and dermal area, as well as enhanced neutrophil and macrophage content. Flow cytometry demonstrated increased levels of granulocytes, T cells and monocytes/macrophages in the ear skin, with T cells identified as the main cellular source of IL‐17A. Evaluation of mRNA and protein showed time‐dependent, increased levels of the IL‐23/IL‐17 pathway and inflammatory/microbial cytokines/chemokines in the ear which differed kinetically from circulating levels. An anti‐IL‐23p40 antibody was assessed following both prophylactic administration and administration once the disease was established. Prophylactic dosing completely prevented the development of the ear phenotype across endpoints. Treatment administration showed a dose‐related response, with a maximum inhibition of 64–94%, depending on endpoint. These data demonstrate that the IL‐23 MC model is a useful approach to study IL‐23/IL‐17‐driven skin inflammation and may facilitate preclinical assessment of novel therapies.

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ACT1 Is Required for Murine IL-23–Induced Psoriasiform Inflammation Potentially Independent of E3 Ligase Activity

Lipovsky

Slivka

et al. 2021

Journal of Investigative Dermatology

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Mechanistic and pharmacological assessment of murine IL-23 mediated psoriasiform dermatitis; implications for drug discovery

Abstract: Collectively, our studies indicate that a 5 day model of IL-23 psoriasiform dermatitis can be used to assess the pharmacology of novel small molecules/biologics in the treatment of PsO.

Cited by 14 publications

References 33 publications

IL‐36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis

IL‐36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis

Characterization of psoriasiform dermatitis induced by systemic injection of interleukin‐23 minicircles in mice

ACT1 Is Required for Murine IL-23–Induced Psoriasiform Inflammation Potentially Independent of E3 Ligase Activity

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