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Non-classical monocytes as mediators of tissue destruction in arthritis

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Puchner A1, Saferding V1, Bonelli M1, Mikami Y2, Hofmann M1, Brunner JS1, Caldera M3, Goncalves-Alves E1, Binder NB1, Fischer A1, Simader E1, Steiner CW1, Leiss H1, Hayer S1, Niederreiter B1, Karonitsch T1, Koenders MI4, Podesser BK5, O'Shea JJ2, Menche J3, Smolen JS1, Redlich K1, Bl├╝ml S1,6. Ann Rheum Dis. 2018 Jun 29. pii: annrheumdis-2018-213250. doi: 10.1136/annrheumdis-2018-213250. [Epub ahead of print]

Abstract

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1 Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

2 Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, Bethesda, Maryland, USA.

3 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

4 Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.

5 Department of Biomedical Research, Medical University of Vienna, Vienna, Austria.

6 Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria.

Abstract

OBJECTIVES: Bone destruction in rheumatoid arthritis is mediated by osteoclasts (OC), which are derived from precursor cells of the myeloid lineage. The role of the two monocyte subsets, classical monocytes (expressing CD115, Ly6C and CCR2) and non-classical monocytes (which are CD115 positive, but low in Ly6C and CCR2), in serving as precursors for OC in arthritis is still elusive.

METHODS: We investigated CCR2-/- mice, which lack circulating classical monocytes, crossed into hTNFtg mice for the extent of joint damage. We analysed monocyte subsets in hTNFtg and K/BxN serum transfer arthritis by flow cytometry. We sorted monocyte subsets and analysed their potential to differentiate into OC and their transcriptional response in response to RANKL by RNA sequencing. With these data, we performed a gene ontology enrichment analysis and gene set enrichment analysis.

RESULTS: We show that in hTNFtg arthritis local bone erosion and OC generation are even enhanced in the absence of CCR2. We further show the numbers of non-classical monocytes in blood are elevated and are significantly correlated with histological signs of joint destruction. Sorted non-classical monocytes display an increased capacity to differentiate into OCs. This is associated with an increased expression of signal transduction components of RANK, most importantly TRAF6, leading to an increased responsiveness to RANKL.

CONCLUSION: Therefore, non-classical monocytes are pivotal cells in arthritis tissue damage and a possible target for therapeutically intervention for the prevention of inflammatory joint damage.