Interleukin-36 family dysregulation drives joint inflammation and therapy response in psoriatic arthritis

Abstract

Objectives IL-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. Methods Synovial 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. Results PsA 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. Conclusion The 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.

Novel immune cell phenotypes in spondyloarthritis pathogenesis

“…Very recently, Boutet and colleagues explored the role of the neutrophil activated cytokine IL-36, an under investigated member of the IL-1 family, in the pathogenesis and treatment response in PsA [104]. To note, bulk RNA sequencing performed on early treatment naïve PsA and RA synovial tissue demonstrated a strong neutrophil signature in PsA tissues, which was consistent with immunohistochemical staining for neutrophil-derived proteins.…”

“…To note, bulk RNA sequencing performed on early treatment naïve PsA and RA synovial tissue demonstrated a strong neutrophil signature in PsA tissues, which was consistent with immunohistochemical staining for neutrophil-derived proteins. In the same cohort, it was observed that there was an imbalance between IL-36 agonists and antagonists that correlated with a poorer response to DMARDs [104].…”

“…Neutrophil infiltration has been classically observed in the course of arthritis. However, multiple reports observed a preferential neutrophil involvement in PsA compared to RA, and both TNFα and IL-17 are known chemoattractants for neutrophils [103,104].…”

Exploring the Role of IL-36 Cytokines as a New Target in Psoriatic Disease

“…IL-36α is expressed and produced by macrophages and plasma cells in the synovium of PsA patients, with expression levels similar to those in rheumatoid arthritis (RA) [ 46 , 47 ]. However, Boutet and colleagues found a deficient expression of IL-36Ra and IL-38 in comparison to RA, permitting an easier activation of downstream pro-inflammatory cascades by IL-36α in PsA [ 47 ]. Evidence of IL-36 activation in PsA was underpinned by a higher expression of cathepsin G and neutrophil elastase in PsA [ 47 ].…”

Serum IL‐36 cytokines levels in type 2 diabetes mellitus patients and their association with obesity, insulin resistance, and inflammation

“…Recent studies found that IL‐36 cytokines play a key role in obesity‐related metabolic disorders, low‐grade inflammation, and IR. Several studies showed that IL‐36 cytokines have effects on psoriasis, arthritis, and systemic lupus erythematosus, but there are few reports on the IL‐36 cytokines in T2DM 4,5 . To explore the clinical relevance of IL‐36 cytokines in T2DM, we determined the serum IL‐36 cytokines concentrations of normal subjects and T2DM patients, and analyzed their relationships with IR, anthropometry, and metabolic parameters.…”