S100A8/A9 increases the mobilization of pro-inflammatory Ly6Chigh monocytes to the synovium during experimental osteoarthritis

• Published in: Arthritis research & therapy 2017-09, Vol.19 (1), p.217-217, Article 217
• Main Authors: Cremers, Niels A. J., van den Bosch, Martijn H. J., van Dalen, Stephanie, Di Ceglie, Irene, Ascone, Giuliana, van de Loo, Fons, Koenders, Marije, van der Kraan, Peter, Sloetjes, Annet, Vogl, Thomas, Roth, Johannes, Geven, Edwin J. W., Blom, Arjen B., van Lent, Peter L. E. M.
• Format: Article
• Language: English
• Subjects: Animals; Arthritis; Atherosclerosis; Chemokines; Collagenase-induced osteoarthritis; Development and progression; Experiments; Genetic aspects; Growth factors; Housing conditions; Inflammation; Ly6C high/low monocytes; Mobilization; Monocytes; Osteoarthritis; Physiological aspects; Proteins; S100; Synovial fluid; Systemic effects
• ISSN: 1478-6362; 1478-6354; 1478-6362
• DOI: 10.1186/s13075-017-1426-6

Background Monocytes are dominant cells present within the inflamed synovium during osteoarthritis (OA). In mice, two functionally distinct monocyte subsets are described: pro-inflammatory Ly6C.sup.high and patrolling Ly6C.sup.low monocytes. Alarmins S100A8/A9 locally released by the synovium during inflammatory OA for prolonged periods may be dominant proteins involved in stimulating recruitment of Ly6C.sup.high monocytes from the circulation to the joint. Our objective was to investigate the role of S100A8/A9 in the mobilization of Ly6C.sup.high and Ly6C.sup.low monocytic populations to the inflamed joint in collagenase-induced OA (CiOA). Method S100A8 was injected intra-articularly to investigate monocyte influx. CiOA was induced by injection of collagenase into knee joints of wild-type C57BL/6 (WT), and S100a9.sup.-/- mice. Mice were sacrificed together with age-matched saline-injected control mice (n = 6/group), and expression of monocyte markers, pro-inflammatory cytokines, and chemokines was determined in the synovium using ELISA and RT-qPCR. Cells were isolated from the bone marrow (BM), spleen, blood, and synovium and monocytes were identified using FACS. Results S100A8/A9 was highly expressed during CiOA. Intra-articular injection of S100A8 leads to elevated expression of monocyte markers and the monocyte-attracting chemokines CCL2 and CX3CL1 in the synovium. At day 7 (d7) after CiOA induction in WT mice, numbers of Ly6C.sup.high, but not Ly6C.sup.low monocytes, were strongly increased (7.6-fold) in the synovium compared to saline-injected controls. This coincided with strong upregulation of CCL2, which preferentially attracts Ly6C.sup.high monocytes. In contrast, S100a9.sup.-/- mice showed a significant increase in Ly6C.sup.low monocytes (twofold) within the synovium at CiOA d7, whereas the number of Ly6C.sup.high monocytes remained unaffected. In agreement with this finding, the Ly6C.sup.low mobilization marker CX3CL1 was significantly higher within the synovium of S100a9.sup.-/- mice. Next, we studied the effect of S100A8/A9 on release of Ly6C.sup.high monocytes from the BM into the circulation. A 14% decrease in myeloid cells was found in WT BM at CiOA d7. No decrease in myeloid cells in S100a9.sup.-/- BM was found, suggesting that S100A8/A9 promotes the release of myeloid populations from the BM. Conclusion Induction of OA locally leads to strongly elevated S100A8/A9 expression and an elevated influx of Ly6C.sup.high monocytes from the BM to