“High mobility group box 1” (HMGB1) is a well-known nuclear protein that stabilizes DNA and facilitates gene transcription. Additionally, cell stress or death induces the release of HMGB1 outside the cell membrane, where HMGB1 functions as an alarmin, causing an inflammatory response in combination with other cytokines, DAMPs, and PAMPs. Recently, it has been reported that the proinflammatory activity of HMGB1 is dependent on the redox status of its three cysteine residues. These residues can be in the reduced, disulfide, or oxidized form. The reduced exert a chemoattractive effect and the disulfide form has proinflammatory cytokine activity but oxidized form has no inflammatory activity. However, the effect of HMGB1 for keratinocytes considering its redox status was not well elucidated. In this study, we confirmed the proinflammatory effect of HMGB1 in keratinocytes, and surprisingly, we found a suppressive effect of reduced-HMGB1 under the inflammatory condition in keratinocytes. To prove this, we focused on downstream components of the poly(I:C)-TLR3, RIG-I, and MDA5 pathways, including IκBα, NF-κB p65, MAPK, and IRF3, and assessed whether HMGB1 acts as a suppressor via these pathways. Application of reduced-HMGB1 before, but not after, poly (I:C) stimulation exerted a suppressive effect. In addition, this phenomenon was observed with reduced-HMGB1 but not disulfide-HMGB1, which suggests that the redox status of exogenous HMGB1 is important for its suppressive effect. These findings suggest that reduced-HMGB1 could be a new candidate as an inflammation suppressor in keratinocytes.

Newly discovered function of reduced-HMGB1 as an inflammation suppressor in keratinocytes