Background Over the last years, the differentiation and activation of MDSC under tumor conditions has been studied extensively. Various tumor-derived factors have been identified in promoting the accumulation of this suppressive cell population. Recent findings determined the two alarmins S100A8 and S100A9 as important factors in the differentiation of MDSC during tumor conditions. However, little is known about the S100A8/A9 driven expansion and activation, as well as the relevance of these cells in autoimmune diseases such as rheumatoid arthritis.
Objectives We therefore analyzed the mechanisms involved in S100A8/A9 driven MDSC accumulation and their functional importance in a mouse model of rheumatoid arthritis.
Methods To investigate the effect of S100A8/A9 on MDSC differentiation, bone marrow cells from wild type (wt), S100A9 knockout (A9ko) and S100A9 transgenic (A9tg) mice were analyzed. Accumulation of MDSC and their phenotypical characterization was performed by FACS analysis and functional characterization including arginase activity, NO- and ROS-production and T cell proliferation assays.
The role of S100A8/A9 and MDSC in arthritis was investigated using the collagen-induced arthritis (CIA) mouse model. Accumulation of MDSC in different organs was analyzed by FACS and systemic S100A8/A9 levels were measured by ELISA. Ex vivo functional analysis of purified MDSC was performed to assess the potential of these MDSC to inhibit T cell responses.
Results Our in vitro studies reveal that, in the presence of S100A8, myeloid progenitor cells differentiate to immature cells that phenotypically as well as functionally resemble MDSC. These cells are characterized by co-expression and up-regulation of arginase activity, NO- and ROS-production, and exhibit strong suppressive effects on the proliferation of both CD4- and CD8-positive T cells. Furthermore, accumulation of MDSC by extracellular S100A8 was found to be mediated via the Toll-like receptor 4 signaling pathway. In addition, lack of intracellular S100A8/A9 results in a decreased number of MDSC as well as a reduced suppressive activity of these cells, implying a dual role of these proteins for MDSC differentiation and function.
Investigating the role of S100A8/A9 and MDSC in a mouse model of CIA, a clear correlation between disease scores, MDSC numbers and systemic S100A8/A9 levels was observed. Furthermore, disease activity was reduced in wt and A9tg mice compared to A9ko mice and was in line with an increased accumulation of MDSC in the lymph nodes. Next to an enhanced suppressive activity of MDSC isolated from lymph nodes of wt and A9tg mice, these MDSC promoted the accumulation of regulatory T cells (Treg) whilst suppressing the differentiation of TH17 cells. In contrast, MDSC isolated from lymph nodes of A9ko mice had no effect on Treg differentiation and did not inhibit TH17 emergence.
Conclusions Our in vitro results clearly show a S100A8/A9 dependent accumulation of cells that phenotypically as well as functionally resemble MDSC also under non-tumor conditions. In vivo data strongly support the importance of these findings. By influencing MDSC accumulation and function, S100A8/A9 is critically involved in regulating the disease outcome in rheumatoid arthritis, implying an important role of S100A8/A9 derived MDSC in regulating immune reactions during autoimmune diseases.
Disclosure of Interest None declared