S100A8/A9-alarmin promotes local myeloid-derived suppressor cell activation restricting severe autoimmune arthritis
Meike von Wulffen,
Veronika Luehrmann,
Stefanie Robeck,
Antonella Russo,
Lena Fischer-Riepe,
Martijn van den Bosch,
Peter van Lent,
Karin Loser,
Dmitry I. Gabrilovich,
Sven Hermann,
Johannes Roth,
Thomas Vogl
Affiliations
Meike von Wulffen
Institute of Immunology, University of Münster, Münster, Germany; Interdisciplinary Center of Clinical Research (IZKF), University of Münster, Münster, Germany
Veronika Luehrmann
Institute of Immunology, University of Münster, Münster, Germany
Stefanie Robeck
Institute of Immunology, University of Münster, Münster, Germany
Antonella Russo
Institute of Immunology, University of Münster, Münster, Germany
Lena Fischer-Riepe
Institute of Immunology, University of Münster, Münster, Germany
Martijn van den Bosch
Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands
Peter van Lent
Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands
Karin Loser
Department of Human Medicine, University of Oldenburg, Oldenburg, Germany
Dmitry I. Gabrilovich
AstraZeneca Oncology R&D, Gaithersburg, MD 20878, USA
Sven Hermann
European Institute for Molecular Imaging (EIMI), University of Münster, Münster, Germany
Johannes Roth
Institute of Immunology, University of Münster, Münster, Germany; Interdisciplinary Center of Clinical Research (IZKF), University of Münster, Münster, Germany
Thomas Vogl
Institute of Immunology, University of Münster, Münster, Germany; Interdisciplinary Center of Clinical Research (IZKF), University of Münster, Münster, Germany; Corresponding author
Summary: Immune-suppressive effects of myeloid-derived suppressor cells (MDSCs) are well characterized during anti-tumor immunity. The complex mechanisms promoting MDSC development and their regulatory effects during autoimmune diseases are less understood. We demonstrate that the endogenous alarmin S100A8/A9 reprograms myeloid cells to a T cell suppressing phenotype during autoimmune arthritis. Treatment of myeloid precursors with S100-alarmins during differentiation induces MDSCs in a Toll-like receptor 4-dependent manner. Consequently, knockout of S100A8/A9 aggravates disease activity in collagen-induced arthritis due to a deficit of MDSCs in local lymph nodes, which could be corrected by adoptive transfer of S100-induced MDSCs. Blockade of MDSC function in vivo aggravates disease severity in arthritis. Therapeutic application of S100A8 induces MDSCs in vivo and suppresses the inflammatory phenotype of S100A9ko mice. Accordingly, the interplay of T cell-mediated autoimmunity with a defective innate immune regulation is crucial for autoimmune arthritis, which should be considered for future innovative therapeutic options.
