Abstract
ObjectivesIL-36 agonists are pro-inflammatory cytokines involved in the pathogenesis of psoriasis. However, their role in the pathogenesis of arthritis and treatment response to DMARDs in PsA remains uncertain. Therefore, we investigated the IL-36 axis in the synovium of early, treatment-naïve PsA, and for comparison RA patients, pre- and post-DMARDs therapy.MethodsSynovial tissues were collected by US-guided biopsy from patients with early, treatment-naïve PsA and RA at baseline and 6 months after DMARDs therapy. IL-36 family members were investigated in synovium by RNA sequencing and immunohistochemistry, and expression levels correlated with DMARDs treatment response ex vivo. Additionally, DMARDs effects on IL-36 were investigated in vitro in fibroblast-like synoviocytes.ResultsPsA synovium displayed a reduced expression of IL-36 antagonists, while IL-36 agonists were comparable between PsA and RA. Additionally, neutrophil-related molecules, which drive a higher activation of the IL-36 pathway, were upregulated in PsA compared with RA. At baseline, the synovial expression of IL-36α was significantly higher in PsA non-responders to DMARDs treatment, with the differential expression being sustained at 6 months post-treatment. In vitro, primary PsA-derived fibroblasts were more responsive to IL-36 stimulation compared with RA and, importantly, DMARDs treatment increased IL-36 expression in PsA fibroblasts.ConclusionThe impaired balance between IL-36 agonists–antagonists described herein for the first time in PsA synovium and the decreased sensitivity to DMARDs in vitro may explain the apparent lower efficacy of DMARDs in PsA compared with RA. Exogenous replacement of IL-36 antagonists may be a novel promising therapeutic target for PsA patients.
Highlights
PsA is a chronic seronegative SpA affecting up to 30% of patients with skin psoriasis and characterized by theThe IL-36 family, part of the larger IL-1 cytokine family, includes three agonists, IL-36a, IL-36b and IL-36g, and two inhibitors, IL-36RA and IL-38
We found an impaired expression of IL-36 antagonists IL-36RA and IL-38 in PsA synovium compared with RA, with significantly lower expression confirmed at both RNA and protein level by immunohistochemistry (Fig. 1B and C)
To test whether in addition to the lower levels of inhibitors found in PsA compared with RA synovitis there was an increased IL-36 activation, we investigated the expression of neutrophil-related genes and Neutrophil elastase and Cathepsin G, the two serine proteinases involved in the maturation of IL-36a [12]
Summary
PsA is a chronic seronegative SpA affecting up to 30% of patients with skin psoriasis and characterized by theThe IL-36 family, part of the larger IL-1 cytokine family, includes three agonists, IL-36a, IL-36b and IL-36g, and two inhibitors, IL-36RA and IL-38. PsA is a chronic seronegative SpA affecting up to 30% of patients with skin psoriasis and characterized by the. IL38 is a broader inhibitor able to antagonize to IL-36 cytokines, Toll-Like Receptor and the IL-1-mediated signalling pathway [68]. Like IL-1, IL-36 cytokines need to be processed to be fully active and neutrophils proteases have been identified as the main regulators of IL-36 axis activation [913]. In mouse models of psoriasis, IL-36a, in crosstalk with IL-1 and Th17, promotes neutrophil recruitment and chemokines production [17], while mice lacking IL-1R1 and IL-36a are almost disease-free [18]. The absence of the IL-36 inhibitor IL-36RA causes acute generalized pustular psoriasis [19], and IL-36R inhibitors are currently on trial for treating psoriasis after successful studies in mice [20, 21]
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