During the resolution of acute inflammation, macrophages undergo reprogramming from pro-inflammatory, to anti-inflammatory/reparative, and eventually to pro-resolving macrophages. Galectin-1 (Gal-1) is a bona fide pro-resolving lectin while interferon β (IFN-β) was recently shown to facilitate macrophage reprogramming and resolution of inflammation. In this study, we found Gal-1^null mice exhibit a hyperinflammatory phenotype during the resolution of zymosan A-induced peritonitis but not during the early inflammatory response. This phenotype was characterized by reduced macrophage numbers, increased secretion of pro-inflammatory cytokines, such as interleukin-12 (IL-12), and reduced secretion of anti-inflammatory cytokines, such as interleukin-10 (IL-10). In addition, we found a delayed expression of the pro-resolving enzyme 12/15-lipoxygenase in macrophages and heightened levels of the inflammatory protease proteinase-3 (PR3) in peritoneal fluids from Gal-1^null mice. Moreover, we observed sex-dependent differences in the inflammatory profile of Gal-1^null mice. Notably, we found that IFN-β levels were reduced in resolution-phase exudates from Gal-1^null mice. Administration of IFN-β in vivo or ex vivo treatment was able to rescue, at least in part, the hyperinflammatory profile of Gal-1^null mice. In particular, IFN-β recovered a subset of F4/80⁺GR-1⁺ macrophages, restored IL-12 and IL-10 secretion from macrophages to WT values and diminished abnormal peritoneal PR3 levels in Gal-1^null mice. In conclusion, our results revealed a new Gal-1-IFN-β axis that facilitates the resolution of inflammation and might restrain uncontrolled inflammatory disorders.

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