IL-6 receptor blockade prevents polarization of pro-fibrotic macrophages in myeloid-rich RA synovial tissue

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B861
Abstract ID: 4813

Presenting Author:
Ian Mantel , PhD Candidate at Weill Cornell Med. Grad. Sch. of Med. Sci., Hosp. for Special Surgery

Abstract:

In rheumatoid arthritis (RA), macrophages represent key therapeutic targets due to their ability to drive inflammation. Interestingly, new subtypes of RA have been identified, based on distinct patterns of cell types in the joint, wherein one-third of patients demonstrate an enrichment of pro-fibrotic SPP1^hiCLEC5A^hi macrophages. We set out to understand what drives the formation of these macrophages in RA joints, and how anti-inflammatory medications used to treat RA may differentially affect joints with pro-fibrotic versus pro-inflammatory macrophages. In RA joints with an abundance of SPP1^hiCLEC5A⁺ macrophages, TGFB1 expressing endothelial cells and stromal cells expressing IL6 and CSF1 are co-enriched. In an in vitro culture system, we found that the SPP1^hiCLEC5A⁺ macrophage phenotype could result from exposure to factors from synovial fibroblasts along with TGF-β. Blockade of the IL-6 receptor with tocilizumab inhibited the generation of the fibroblast-directed SPP1^hiCLEC5A⁺ macrophage state. This differed from the inflammatory HBEGF⁺IL1B⁺ macrophage state, found in joints with extensive T and B cell aggregates. Interestingly, in a clinical trial that used tocilizumab, joint tissue transcriptomics demonstrated a reduction in SPP1^hiCLEC5A⁺ cell signatures. This study highlights the importance of making treatment decisions for RA patients informed by the cellular composition of the affected tissue.