Cytokine “fine tuning” of enthesis tissue homeostasis as a pointer to spondyloarthritis pathogenesis with a focus on relevant TNF and IL-17 targeted therapies

Abstract

A curious feature of axial disease in ankylosing spondylitis (AS) and related non-radiographic axial spondyloarthropathy (nrAxSpA) is that spinal inflammation may ultimately be associated with excessive entheseal tissue repair with new bone formation. Other SpA associated target tissues including the gut and the skin have well established paradigms on how local tissue immune responses and proven disease relevant cytokines including TNF and the IL-23/17 axis contribute to tissue repair. Normal skeletal homeostasis including the highly mechanically stressed entheseal sites is subject to tissue microdamage, micro-inflammation and ultimately repair. Like the skin and gut, healthy enthesis has resident immune cells including ILCs, γδ T cells, conventional CD4+ and CD8+ T cells and myeloid lineage cells capable of cytokine induction involving prostaglandins, growth factors and cytokines including TNF and IL-17 that regulate these responses. We discuss how human genetic studies, animal models and translational human immunology around TNF and IL-17 suggest a largely redundant role for these pathways in physiological tissue repair and homeostasis. However, disease associated immune system overactivity of these cytokines with loss of tissue repair “fine tuning” is eventually associated with exuberant tissue repair responses in AS. Conversely, excessive biomechanical stress at spinal enthesis or peripheral enthesis with mechanically related or degenerative conditions is associated with a normal immune system attempts at cytokine fine tuning, but in this setting, it is commensurate to sustained abnormal biomechanical stressing. Unlike SpA, where restoration of aberrant and excessive cytokine “fine tuning” is efficacious, antagonism of these pathways in biomechanically related disease may be of limited or even no value.

Why Inhibition of IL-23 Lacked Efficacy in Ankylosing Spondylitis

“…We also found that this IL-23 secretion could be attenuated by the addition of PDE4 blockers which may be relevant translationally since antagonism of this pathway shows efficacy for peripheral enthesitis in PsA in man (56). Both TNF and IL-17A are able to also induce osteogenesis in vitro in MSC from the spinal enthesis (60,61).…”

Warum die Hemmung von IL-23 bei ankylosierender Spondylitis nicht wirksam war

“…Zudem stellten wir fest, dass sich diese IL-23-Sekretion durch die Gabe von Phosphodiesterase-4 (PDE4)-Blockern abschwächen ließ, was translational bedeutsam sein könnte, da die Antagonisierung dieses Signalwegs beim Menschen Wirksamkeit bei peripherer Enthesitis bei PsA zeigt [56]. Sowohl TNF als auch IL-17A sind in der Lage, die Osteogenese in vitro in mesenchymalen Stammzellen (mesenchymal stem cells, MSCs) aus der spinalen Enthese zu induzieren [60, 61].…”

From Bed to Bench and Back: TNF-α, IL-23/IL-17A, and JAK-Dependent Inflammation in the Pathogenesis of Psoriatic Synovitis

“…This clinical heterogeneity is reflected in complex pathophysiology, knowledge of which is crucial to hypothesizing a therapeutic approach targeting the ongoing pathological process ( Veale and Fearon, 2018 ; Scher et al, 2019 ; Russell et al, 2021 ). Infiltration of both innate and adaptive immune cells in different target organs and tissues results in significant production of different proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, IL-22, IL-23, IL-17A, and IL-18, inducing further inflammatory mediators release and damage progression.…”