1,25-Dihydroxyvitamin D Inhibits LPS-Induced High-Mobility Group Box 1 (HMGB1) Secretion via Targeting the NF-E2-Related Factor 2–Hemeoxygenase-1–HMGB1 Pathway in Macrophages

1,25-Dihydroxyvitamin D [1,25(OH)(2)D(3)] is recognized as a key mediator of inflammatory diseases, including sepsis. Clinical studies demonstrate that 1,25 (OH)(2)D(3) protects patients from sepsis, but clinical treatment with 1,25(OH)(2)D(3) is rare. In this study, we report that 1,25(OH)(2)D(3) treatment has beneficial effects and improves the survival rate in LPS-induced mouse sepsis model by blocking the secretion of high-mobility group box 1 (HMGB1), a key late regulator of sepsis. LPS-induced HMGB1 secretion is attenuated by 1,25(OH)(2)D(3) via blocking HMGB1 translocation from the nucleus to the cytoplasm in macrophages. 1,25(OH)(2)D(3) can induce the expression of hemeoxygenase-1 (HO-1), which is essential for blocking HMBG1 nuclear translocation and its secretion. When siHO-1 or an HO-1 inhibitor are used, the effect of 1,25(OH)(2)D(3) on inhibition of HMGB1 secretion is suppressed. Considering that HO-1 is a downstream gene of NF-E2-related factor 2 (Nrf2), we further confirm that Nrf2 activation can be activated by 1,25(OH)(2)D(3) upon LPS exposure. Together, we provide evidence that 1,25(OH)(2)D(3) attenuates LPS-induced HMGB1 secretion via the Nrf2/HO-1 pathway in macrophages.