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T-cell instructed monocyte activation is a key pathological feature in Ankylosing Spondylitis and provides novel therapeutic opportunities

ABSTRACT: Activated T-cells potently stimulated monocytes from patients with AS to produce IL-1β and IL-23. These in turn act back on T cells to enhance Th17 responses. T-cell activated monocytes are heterogeneous but include a subset of “super proinflammatory monocytes” not induced by LPS activation and for enriched for AS risk genes, including ERN1. Importantly, we identify a population of CD14+ myeloid cells highly enriched in AS synovial fluid strikingly similar gene expression profile high levels of CCL3, CCL4, IL1B, TNF, CXCL2, strongly suggesting T cell activation in vivo. a T-cell instructed monocyte activation can be inhibited by genetic or chemical suppression of ERN1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE232131 | GEO | 2024/01/01

REPOSITORIES: GEO

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Project description:We have compared synovial biopsies from ankylosing spondylitis and undifferentiated spondylitis patients with healthy controls and osteoarthritis patients Objective: In spondylarthropies, whole-genome gene expression profiling studies have been limited to peripheral blood to date. By undertaking a study in knee synovial biopsies from spondylarthropy (SpA) and ankylosing spondylitis (AS) patients we aimed to identified joint-specific candidate genes and pathways. These pathways may mediate systemic inflammation driven joint damaging processes and more specifically, the osteoproliferation that is characteristic of these conditions. Methods: RNA was extracted from six seronegative SpA, two AS, three osteoarthritis (OA) and four normal control knee synovial biopsies. Whole genome expression profiling was undertaken using the Illumina DASL system, which assays 24000 cDNA probes. Differentially expressed candidate genes were then validated using quantitative PCR and immunohistochemistry. Results: 416 differentially expressed genes were identified that clearly delineated between AS/SpA and control groups. Pathway analysis showed altered gene-expression in oxidoreductase activity, osteoblast activity, B-cell associated, matrix catabolic, and metabolic pathways. The inflammatory mediator, MMP3, was strongly upregulated in AS/SpA samples and the Wnt pathway inhibitors DKK3 and Kremen1 were downregulated. Conclusion: Pathways mediating both systemic inflammation as well as local tissue changes were identified. This suggests initial systemic inflammation in spondylarthropies transfers to and persists in the local joint environment, subsequently mediating changes in genes directly involved in the destructive tissue remodelling. Fifteen knee synovial biopsy tissue samples consisting of six seronegative spondyloarthropy (SpA), two ankylosing spondylitis (AS), three osteoarthritis (OA) and four normal control biopsies were obtained from the Synovial Tissue Bank at the Repatriation General Hospital in Adelaide, South Australia with the appropriate ethical approval (Supplementary Table 1). All patients provided informed written consent.

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T-cell instructed monocyte activation is a key pathological feature in Ankylosing Spondylitis and provides novel therapeutic opportunities

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