The Role of the IL-23/IL-17 Axis in Disease Initiation in Spondyloarthritis: Lessons Learned From Animal Models.

Mohamed Mandour,Sijia Chen,Marleen G H Van De Sande

doi:10.3389/fimmu.2021.618581

Abstract

Spondyloarthritis (SpA) is a spectrum of chronic inflammatory joint diseases that frequently presents with inflammation of the axial skeleton, peripheral joints, entheses, skin, and gut. Understanding SpA pathogenesis has been proven challenging due to the limited availability of human target tissues. In recent years, the interleukin (IL)-23/IL-17 pathway has been implicated in the pathogenesis of SpA, in addition to the Tumor Necrosis Factor Alpha (TNF-α) cytokine. The underlying molecular mechanisms by which the IL-23/IL-17 pathway triggers disease initiation, both in the joints as well as at extra-musculoskeletal sites, are not precisely known. Animal models that resemble pathological features of human SpA have provided possibilities for in-depth molecular analyses of target tissues during various phases of the disease, including the pre-clinical initiation phase of the disease before arthritis and spondylitis are clinically present. Herein, we summarize recent insights gained in SpA animal models on the role of the IL-23/IL-17 pathway in immune activation across affected sites in SpA, which include the joint, entheses, gut and skin. We discuss how local activation of the IL-23/IL-17 axis may contribute to the development of tissue inflammation and the onset of clinically manifest SpA. The overall aim is to provide the reader with an overview of how the IL-23/IL-17 axis could contribute to the onset of SpA pathogenesis. We discuss how insights from animal studies into the initiation phase of disease could instruct validation studies in at-risk individuals and thereby provide a perspective for potential future preventive treatment.

Highlights

Spondyloarthritis (SpA) is a chronic inflammatory joint disease characterized by inflammation and new bone formation which results in structural damage
In accordance with the insights from the M.tb HLAB27 study [24, 27], Interleukin 23 (IL-23) plays an important role in the onset of SpA-like pathology in many animal models, even before clinical joint manifestations are present, which is in clear contrast with the absence of any significant clinical effect as observed when blocking IL23R in diseased rats [24] or with blocking of IL-23p19 in AS patients [25]
While animal models provide an ideal basis for in-depth molecular analysis of target tissues in SpA to elucidate causal relationships between the upregulation of specific immune pathways and development of key SpA features, complimentary studies performing serial advanced molecular imaging or biosample collection in individuals with an increased risk of developing SpA or psoriatic arthritis (PsA), or in patients who have been recently diagnosed withSpA, are essentially required if we want to translate findings in animal models of SpA to human disease

Summary

Introduction

Spondyloarthritis (SpA) is a chronic inflammatory joint disease characterized by inflammation and new bone formation which results in structural damage. The disease phenotype in this model resembles human SpA as these rats develop signs of arthritis and spondylitis, with inflammation and new bone formation.

Results

Conclusion