AUTHOR=Fujikawa Yoshikazu , Sendo Sho , del Peral Fanjul Alfonso , Yamada Hirotaka , Uto Kenichi , Yamamoto Yuzuru , Nagamoto Takumi , Morinobu Akio , Saegusa Jun 

TITLE=Myeloid-derived suppressor cell-derived osteoclasts with bone resorption capacity in the joints of arthritic SKG mice

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1168323

DOI=10.3389/fimmu.2024.1168323

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells with immunosuppressive functions. It is known that MDSCs are expanded at inflammatory sites after migrating from bone marrow (BM) or spleen (Sp). In chronic inflammatory diseases such as rheumatoid arthritis (RA), previous reports indicate that MDSCs are increased in BM and Sp, but detailed analysis of MDSCs in inflamed joints is very limited.</p></sec><sec><title>Objective</title><p>The purpose of this study is to characterize the MDSCs in the joints of mice with autoimmune arthritis.</p></sec><sec><title>Methods</title><p>We sorted CD11b<sup>+</sup>Gr1<sup>+</sup> cells from joints (Jo), bone marrow (BM) and spleen (Sp) of SKG mice with zymosan (Zym)-induced arthritis and investigated differentially expressed genes (DEGs) by microarray analysis. Based on the identified DEGs, we assessed the suppressive function of CD11b<sup>+</sup>Gr1<sup>+</sup> cells from each organ and their ability to differentiate into osteoclasts.</p></sec><sec><title>Results</title><p>We identified MDSCs as CD11b<sup>+</sup>Gr1<sup>+</sup> cells by flow cytometry and morphological analysis. Microarray analysis revealed that Jo-CD11b<sup>+</sup>Gr1<sup>+</sup> cells had different characteristics compared with BM-CD11b<sup>+</sup>Gr1<sup>+</sup> cells or Sp-CD11b<sup>+</sup>Gr1<sup>+</sup> cells. Microarray and qPCR analysis showed that Jo-CD11b<sup>+</sup>Gr1<sup>+</sup> cells strongly expressed immunosuppressive DEGs (<italic>Pdl1, Arg1, Egr2</italic> and <italic>Egr3</italic>). Jo-CD11b<sup>+</sup>Gr1<sup>+</sup> cells significantly suppressed CD4<sup>+</sup> T cell proliferation and differentiation <italic>in vitro</italic>, which confirmed Jo-CD11b<sup>+</sup>Gr1<sup>+</sup> cells as MDSCs. Microarray analysis also revealed that Jo-MDSCs strongly expressed DEGs of the NF-κB non-canonical pathway (<italic>Nfkb2</italic> and <italic>Relb</italic>), which is relevant for osteoclast differentiation. In fact, Jo-MDSCs differentiated into osteoclasts <italic>in vitro</italic> and they had bone resorptive function. In addition, intra-articular injection of Jo-MDSCs promoted bone destruction.</p></sec><sec><title>Conclusions</title><p>Jo-MDSCs possess a potential to differentiate into osteoclasts which promote bone resorption in inflamed joints, while they are immunosuppressive <italic>in vitro</italic>.</p></sec>