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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.

frontiers in immunology

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