The sialidase NEU3 promotes pulmonary fibrosis in mice

Abstract

AbstractSialic acid is often the distal sugar on glycoconjugates, and sialidases are enzymes that remove this sugar. In fibrotic lesions in human and mouse lungs, there is extensive desialylation of glycoconjugates, and upregulation of sialidases including the extracellular sialidase NEU3. In the bleomycin model of pulmonary fibrosis, mice lacking NEU3 (Neu3-/-) showed strongly attenuated bleomycin-induced weight loss, lung damage, inflammation, upregulation of TGF-β1, and fibrosis. This indicates that NEU3 is necessary for the full spectrum of bleomycin-induced pulmonary fibrosis. To determine if NEU3 is sufficient for fibrosis, mice not treated with bleomycin were treated with recombinant murine NEU3 or inactive NEU3. Aspiration of NEU3 caused inflammation and fibrosis in the lungs, while inactive NEU3 caused inflammation but not fibrosis. Mice were also treated with NEU3 starting 10 days after bleomycin. In male but not female mice, NEU3 increased inflammation and fibrosis. Inactive NEU3 did not enhance bleomycin-induced lung fibrosis. These results suggest that NEU3 is sufficient to induce fibrosis in the lungs, and that this effect is mediated by NEU3’s enzymic activity.