A CCL20⁺ macrophage subpopulation is the major producer of TNF in axial spondyloarthritis synovium and is driven by CD40L and a myeloid autocrine circuit.

Authors

Jinyi Zhao, Feng Liu, Jiaqi Li, Yao Jiang, Hui Shi, Claudia Worth, Lili Jiang, Davide Simone, Frank Penkava, Hai Fang, Antoni Chan, Jiewei Chen, Dajiang Du, Stephanie G Dakin, Qiang Tong, Lihua Duan, Paul Bowness, Liye Chen

Published in

Annals of the rheumatic diseases. Oct 26, 2026. Epub Oct 26, 2026.

Abstract

Tumour necrosis factor (TNF) and interleukin (IL)-17 are central drivers of axial spondyloarthritis (AxSpA). We previously identified activated CD4+ tissue-resident memory Th17 cells as the principal source of IL-17A/F in AxSpA synovium. We sought to define the cellular source of TNF and mechanisms driving the CCL20⁺ myeloid phenotype in joint and blood.
Single-cell RNA sequencing (scRNA-seq) of synovial tissue from 5 patients with AxSpA was combined with immunofluorescence, synovial-fluid scRNA-seq, and flow cytometry, as well as comparisons with rheumatoid arthritis datasets. Monocyte-derived macrophages from healthy controls (HCs) and patients with AxSpA were cocultured with activated autologous CD4⁺ T cells, with blocking and cytokine experiments defining mechanisms of CCL20⁺ induction. Circulating monocytes were assessed by scRNA-seq and functional assays.
CCL20⁺ macrophages were the predominant source of TNF in AxSpA synovium, with TNF protein confirmed in tissue and synovial fluid. Activated CD4⁺ T cells induced the CCL20⁺ phenotype through CD40L-CD40 signalling and an IL-1β/TNF-α autocrine circuit in HC-derived and AxSpA-derived cells. Baseline AxSpA monocytes showed a higher CCL20⁺ signature than HC monocytes, but this difference largely disappeared after T-cell-mediated induction. Under stimulation, AxSpA monocytes also produced more TNF, IL-6, IL-1β, and IL-23 than HC monocytes, a difference attenuated following IL-1/TNF priming.
CCL20⁺ macrophages are a major CD40L- and IL-1β/TNF-α-driven source of TNF in AxSpA synovium. AxSpA circulating monocytes exhibit heightened basal CCL20⁺ signatures and inflammatory responsiveness that converge towards HC responses after inflammatory priming, supporting circulating CCL20⁺ monocytes as a marker of IL-1β/TNF-α-driven myeloid inflammation.

PMID:
42934005
Bibliographic data and abstract were imported from PubMed on 27 Oct 2026.

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