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

Abstract

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.

Neutrophil exosomes enhance the skin autoinflammation in generalized pustular psoriasis via activating keratinocytes

“…A recent study showed that another key inflammatory cytokine that drives neutrophil migration in GPP is the IL-36 family of cytokines (12), which mainly functions on keratinocytes and myeloid dendritic cells. For instance, several reports have indicated IL-36g acts as a potent proinflammatory mediator and a valuable biomarker of disease activity in psoriasis pathogenesis (45)(46)(47). The IL-36 cytokine family can increase the expression of chemokines including CXCL1, CXCL8, CCL3, CCL5, and CCL20 in keratinocytes to induce the infiltration of more activated leukocytes (48).…”

IL‐17A synergistically enhances TLR3‐mediated IL‐36γ production by keratinocytes: A potential role in injury‐amplified psoriatic inflammation

“…The possible involvement of IL‐36 signalling has recently gained attention in the pathogenesis of psoriasis . Besides acting as a psoriatic biomarker, loss‐of‐function mutations in the IL‐36R antagonist (IL‐36RN) were identified in multiple cohorts of generalized pustular psoriasis patients .…”

“…Besides acting as a psoriatic biomarker, loss‐of‐function mutations in the IL‐36R antagonist (IL‐36RN) were identified in multiple cohorts of generalized pustular psoriasis patients . IL‐36γ regulates keratinocyte proliferation and differentiation to promote skin wound healing, and acts on tissue infiltrating macrophage and actively promotes recruitment of monocytes which cumulatively amplify IL‐23 expression, thus promoting polarization of lymphocytes for increased IL‐17A expression . In psoriasis, keratinocytes are major source of IL‐36γ, and previous observations showed that IL‐36γ had the highest expression level in damaged skin .…”

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

“…The IL‐36 family cytokines consist of Il‐36α, IL‐36β, and IL‐36γ. These cytokines are members of the wider IL‐36 family and are associated with the psoriatic skin inflammation . IL‐36 has inflammatory effects on a range of cells including stroma, T‐cells, fibroblast, and myeloid cells .…”

“…IL‐36 has a growing role in regulating the IL‐23/IL‐17 axis in several diseases . In addition to inducing IL‐23 from myeloid cells, IL‐36 also promotes T‐cell proliferation . Like PsA patients, DITRA patients also benefit from monocyte apheresis treatment .…”