Transcriptomic profiling of osteoarthritis synovial macrophages reveals a tolerized phenotype compounded by a weak corticosteroid response.

Abstract

It is well-known that long-term osteoarthritis prognosis is not improved by corticosteroid treatments. Here we investigate what could underlie this phenomenon by measuring the short term corticosteroid response of osteoarthritic joint synovial macrophages (OA-Mf). We determined the genome-wide transcriptomic response to corticosteroids of end-stage OA-Mf. This was compared with lipopolysaccharide-tolerized and β-glucan-trained circulating blood monocyte-derived macrophage models. Upon corticosteroid stimulation, the trained and tolerized macrophages significantly altered the abundance of 201 and 257 RNA transcripts, respectively. By contrast, by the same criteria, OA-Mf had a very restricted corticosteroid response of only 12 RNA transcripts. Furthermore, while metalloproteinases 1, 2, 3 and 10 expression clearly distinguish OA-Mf from both the tolerized and trained macrophage models, OA-Mf IL-1, chemokine (CXCL) and cytokine (CCL) family member profiles resembled the tolerized macrophage model, with the exception that OA-Mf showed high levels of CCL20. Terminal osteoarthritis joints harbour macrophages with an inflammatory state that closely resembles the tolerized macrophage state, and this is compounded by a weak corticosteroid response capacity that may explain the lack of positive long-term effects of corticosteroid treatment for osteoarthritis patients.