Keisuke Kojima1,*, Tomohiro Arikawa2,*, Naoki Saita1,*, Eisuke Goto1, Shinsuke Tsumura1, Reina Tanaka1, Aiko Masunaga1, Toshiro Niki2,3, Souichi Oomizu2, Mitsuomi Hirashima2,3,# and Hirotsugu Kohrogi1. American Journal of Respiratory and Critical Care Medicine Vol 184. pp. 328-339, (2011)
Rationale: Galectin (Gal)-9 plays a crucial role in the modulation of innate and adaptive immunity.
Objectives: To investigate whether Gal-9 plays a role in a murine acute lung injury (ALI) model.
Methods: C57BL/6 mice were pretreated with Gal-9 by subcutaneous injection 24 and 48 hours before intranasal LPS inoculation.
Measurements and Main Results: Gal-9 suppressed pathological changes of ALI induced by LPS. Gal-9 reduced levels of proinflammatory cytokines and chemokines, such as tumor necrosis factor (TNF)-α, IL-1β, IL-6, and keratinocyte-derived cytokine; decreased neutrophils; and increased IL-10 and CD11b+Gr-1+ macrophages in the bronchoalveolar lavage fluid of ALI mice. In Gal-9–deficient mice, pathological changes of ALI were exaggerated, and the number of neutrophils and the TNF-α level were increased. CD11b+Gr-1+ cells were increased in the spleen of both Gal-9–treated and phosphate-buffered saline (PBS)–treated ALI mice, but only Gal-9 increased the ability of CCR2-expressing macrophages to migrate toward monocyte chemoattractant protein-1. Transfer of CD11b+Gr-1+ macrophages obtained from Gal-9–treated mice ameliorated ALI. CD11b+Gr-1+ macrophages obtained from Gal-9–treated but not PBS-treated mice suppressed TNF-α and keratinocyte-derived cytokine production from LPS-stimulated macrophages, and down-regulated Toll-like receptor-4 (TLR4) and TLR2 expression on thioglycollate-elicited macrophages. Fluorescence-activated cell-sorting analysis revealed that CD14 is negligible on CD11b+Gr-1+ macrophages obtained from Gal-9–treated mice, although those from both groups resembled plasmacytoid dendritic cells (pDCs). Gal-9 down-regulated CD14 on pDC-like macrophages from PBS-treated mice independently of Gal-9/Tim-3 (T-cell immunoglobulin– and mucin domain–containing molecule-3) interaction, resulting in the acquisition of suppressive function, suggesting that the loss of CD14 by Gal-9 is critical for the suppression of pDC-like macrophages.
Conclusions: Gal-9 attenuates ALI by expanding CD14–CD11b+Gr-1+ pDC-like macrophages by preferentially suppressing macrophage functions to release proinflammatory cytokines through TLR4 and TLR2 down-regulation.
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