IL-36γ Is a Strong Inducer of IL-23 in Psoriatic Cells and Activates Angiogenesis.

Charlie Bridgewood,Anne Graham,Tom Macleod,Miriam Wittmann,Martin Stacey,Philip Laws,Sreenivasan Ponnambalam,Anna Berekmeri,Gareth W Fearnley

doi:10.3389/fimmu.2018.00200

Charlie Bridgewood, Anne Graham + Show 7 more

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https://doi.org/10.3389/fimmu.2018.00200

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The IL-1 family member cytokine IL-36γ is recognised as key mediator in the immunopathology of psoriasis, hallmarks of which involve the activation of both resident and infiltrating inflammatory myeloid cells and aberrant angiogenesis. This research demonstrates a role for IL-36γ in both myeloid activation and angiogenesis. We show that IL-36γ induces the production of psoriasis-associated cytokines from macrophages (IL-23 and TNFα) and that this response is enhanced in macrophages from psoriasis patients. This effect is specific for IL-36γ and could not be mimicked by other IL-1 family cytokines such as IL-1α. IL-36γ was also demonstrated to induce endothelial tube formation and branching, in a VEGF-A-dependent manner. Furthermore, IL-36γ-stimulated macrophages potently activated endothelial cells and led to increased adherence of monocytes, effects that were markedly more pronounced for psoriatic macrophages. Interestingly, regardless of stimulus, psoriasis monocytes showed increased adherence to both the stimulated and unstimulated endothelium when compared with monocytes from healthy individuals. Collectively, these findings show that IL-36γ has the potential to enhance endothelium directed leucocyte infiltration into the skin and strengthen the IL-23/IL-17 pathway adding to the growing evidence of pathogenetic roles for IL-36γ in psoriatic responses. Our findings also point to a cellular response, which could potentially explain cardiovascular comorbidities in psoriasis in the form of endothelial activation and increased monocyte adherence.

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Psoriasis is an immune mediated inflammatory disease which affects 2–3% of the world’s population [1]
Differences between treatment groups became more apparent when more time was allowed for the secreted mediator to accumulate. Both 10 and 50 ng/ml IL-36γ induced a significant increase in IL-23 secretion when compared with unstimulated cells, which was further amplified when the macrophages were primed with IFNγ 20 ng/ ml
Myeloid cells are capable of secreting IL-23 and contributing to the IL-23/IL-17 axis, prominent in psoriasis [36]

Summary

Introduction

Psoriasis is an immune mediated inflammatory disease which affects 2–3% of the world’s population [1]. IL-36α, IL-36β, and IL-36γ are members of the IL-1 family of cytokines that signal through a common receptor composed of IL-36 receptor (IL-36R) and IL-1R/AcP to activate NF-κB and MAPKs, such as p38 and JNK, and promote inflammatory responses. IL-36α, IL-36β, and IL-36γ are members of the wider IL-1 family of cytokines These cytokines mediate inflammatory events through the IL-36R and activate NF-κB and MAPKs, such as p38 and JNK in susceptible cells. IL-36R-mediated signal transduction has been shown to induce the release of pro-inflammatory cytokines (e.g., IL-8, TNFα, and IL-6), upregulate antimicrobial peptides and proliferative mediators such as defensins and HB-EGF, as well as T cell attracting or polarising cytokines such as CCL20 and IL-12, respectively [16,17,18,19]

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