IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4−CD8− entheseal resident T cells

Abstract

The spondyloarthropathies are a group of rheumatic diseases that are associated with inflammation at anatomically distal sites, particularly the tendon-bone attachments (entheses) and the aortic root. Serum concentrations of interleukin-23 (IL-23) are elevated and polymorphisms in the IL-23 receptor are associated with ankyosing spondylitis, however, it remains unclear whether IL-23 acts locally at the enthesis or distally on circulating cell populations. We show here that IL-23 is essential in enthesitis and acts on previously unidentified IL-23 receptor (IL-23R)(+), RAR-related orphan receptor γt (ROR-γt)(+)CD3(+)CD4(-)CD8(-), stem cell antigen 1 (Sca1)(+) entheseal resident T cells. These cells allow entheses to respond to IL-23 in vitro-in the absence of further cellular recruitment--and to elaborate inflammatory mediators including IL-6, IL-17, IL-22 and chemokine (C-X-C motif) ligand 1 (CXCL1). Notably, the in vivo expression of IL-23 is sufficient to phenocopy the human disease, with the specific and characteristic development of enthesitis and entheseal new bone formation in the initial complete absence of synovitis. As in the human condition, inflammation also develops in vivo at the aortic root and valve, which are structurally similar to entheses. The presence of these entheseal resident cells and their production of IL-22, which activates signal transducer and activator of transcription 3 (STAT3)-dependent osteoblast-mediated bone remodeling, explains why dysregulation of IL-23 results in inflammation at this precise anatomical site.

Interleukin‐23 Mediates the Intestinal Response to Microbial β‐1,3‐Glucan and the Development of Spondyloarthritis Pathology in SKG Mice

“…We found that both IL-17A and IL-22 promoted peripheral enthesitis, and each contributed to ileitis in a different direction. Our data extend those of Sherlock et al, who found that IL-23 promoted the expression of IL-17 and IL-22 in CD3ϩCD4ϪCD8ϪIL-23RϩROR␥tϩ entheseal cells, with each cytokine participating in the development of enthesitis (15). This differential role of IL-22 in enthesis and ileum is intriguing.…”

“…This differential role of IL-22 in enthesis and ileum is intriguing. While we were not able to study the IL-22-producing cells in the enthesis in curdlantreated SKG mice for technical reasons, current and previously published data suggest that IL-22 is produced by an ROR␥tϩ resident T cell population in the enthesis (15) and by ROR␥tϩCD3Ϫ innate-like and NK-22 cells in the ileum and that each contributes to the pathogenesis of SpA. We show that while anti-IL-23 suppressed both synovitis and enthesitis, inhibition of IL-17 or IL-22 predominantly suppressed enthesitis, indicating that other IL-23-mediated inflammatory mechanisms drive synovitis in response to a ␤-1,3-glucan trigger.…”

“…In support of these findings, overexpression of IL-23 by hepatic injection of Il23 minicircles was recently shown to be sufficient to drive enthesitis and aortitis in mice through IL-23Rϩ innate lymphoid enthesealresident cells in a process involving IL-22 and IL-17 (15). However, it is not clear where IL-23 is produced or how it drives SpA and IBD in genetically prone individuals after an inflammatory trigger.…”

IL12/IL23 Inhibition in the Treatment of Psoriatic Arthritis

“…In the case of psoriasis, antigen driven activation of dendritic cells by interferon α (IFN-α) promotes a Th1 and Th17 cell response in lymph nodes draining the skin [2,3]. These cell subpopulations release a variety of cytokines including interleukin (IL) 17, IL21, IL22, and IL23 and tumor necrosis factor α (TNF-α), which trigger inflammatory cascades in several cell lineages resulting in altered tissue phenotypes, presenting clinically as psoriatic plaques and, as mentioned, about a quarter develop musculoskeletal problems including synovitis, dactylitis, enthesitis, and axial disease [4][5][6].…”

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

“…Systemic overexpression of IL-23 in mice leads to IL-17 production by innate-like T cells present in the enthesis, the bone-tendon interface where much of the inflammation begins in AS, leading to a striking phenocopy of many of the clinical features of AS [61]. Taken together, these data implicate HLA-B27 misfolding with the induction of the UPR as a pathogenic factor in AS upstream of inflammatory cytokine production.…”