CCR2+ monocytic myeloid-derived suppressor cells (M-MDSCs) inhibit collagen degradation and promote lung fibrosis by producing transforming growth factor-β1

Abstract

Monocytes infiltrating scar tissue are predominantly viewed as progenitor cells. Here, we show that tissue CCR2⁺ monocytes have specific immunosuppressive and profibrotic functions. CCR2⁺ monocytic cells are acutely recruited to the lung before the onset of silica-induced fibrosis in mice. These tissue monocytes are defined as monocytic myeloid-derived suppressor cells (M-MDSCs) because they significantly suppress T-lymphocyte proliferation in vitro. M-MDSCs collected from silica-treated mice also express transforming growth factor (TGF)-β1, which stimulates lung fibroblasts to release tissue inhibitor of metalloproteinase (TIMP)-1, an inhibitor of metalloproteinase collagenolytic activity. By using LysMCreCCR2^loxP/loxP mice, we show that limiting CCR2⁺ M-MDSC accumulation reduces the pulmonary contents of TGF-β1, TIMP-1 and collagen after silica treatment. M-MDSCs do not differentiate into lung macrophages, granulocytes or fibrocytes during pulmonary fibrogenesis. Collectively, our data indicate that M-MDSCs contribute to lung fibrosis by specifically promoting a non-degrading collagen microenvironment. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: TIMP; carbon nanotubes; immunosuppression; inflammation; lung fibrosis; myeloid cells; silica.