Background SKG mice develop interstitial lung disease (ILD) resembling human rheumatoid arthritis (RA)–associated ILD. We identified a unique cell population of CD11b+Gr1dim cells in the severely inflamed lungs in SKG mice.
Objectives The aims of this study are to clarify the mechanism behind the lung pathology, and to elucidate the phenotype and function of CD11b+Gr1dim cells in ILD-induced SKG mice.
Methods We assessed the severity of zymosan A-induced ILD in SKG mice histologically, and examined lung-infiltrating cells by Giemsa stain and flow cytometry. Total lung cells and isolated monocytic myeloid-derived suppressor cells (M-MDSCs) were cultured in vitro with GM-CSF (and IL-4). The proliferation of CSFE-labeled naïve T cells co-cultured with isolated CD11b+Gr1dim cells and MDSCs was evaluated by flow cytometry.
Results MDSCs, Th17 cells, and group 1 and 3 innate lymphoid cells (ILC1s and ILC3s) were increased in the lungs; the proportion of these cells varied with ILD severity. In this process, we found that a unique cell population, CD11b+Gr1dim cells, were expanded in the severely inflamed lungs (Figure). About half of the CD11b+Gr1dim cells expressed CD11c and Giemsa stain revealed that they were morphologically dendritic cell (DC)-like. The CD11b+Gr1dim cells were induced from M-MDSCs with GM-CSF in vitro and were considered tolerogenic because they expressed high levels of PD-L1 and suppressed T-cell proliferation. The CD11b+Gr1dim cells have never described previously and termed CD11b+Gr1dim tolerogenic DC-like cells (CD11b+Gr1dimtolDC-LCs). Th17 cells, ILC1s and ILC3s in the inflamed lung produced GM-CSF, which in turn could induce CD11b+Gr1dimtolDC-LCs to reduce inflammation.
Conclusions We identified a unique cell population, termed CD11b+Gr1dimtolDC-LCs, in ILD-induced lungs in SKG mice.
Nishimura K, Saegusa J, Matsuki F, Akashi K, Kageyama G, Morinobu A. Tofacitinib facilitates the expansion of myeloid-derived suppressor cells and ameliorates arthritis in SKG mice. Arthritis Rheumatol 2015;67:893–902.
Shiomi A, Usui T, Ishikawa Y, Shimuzu M, Murakami K, Mimori T. GM-CSF but not IL-17 is critical for the development of severe interstitial lung disease in SKG mice. J. Immunol 2014;193:849–59.
Takenaka MC, Quintana FJ. Tolerogenic dendritic cells. Semin. Immunopahol 2016. doi:10.1007/s00281–016–0587–8.
Acknowledgements The authors thank Shino Tanaka (Department Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine) for providing technical assistance.
Disclosure of Interest None declared