Blockade of HMGB1 Reduces Inflammation and Pruritus in Atopic Dermatitis by Inhibiting Skin Fibroblasts Activation

Int Arch Allergy Immunol. 2024;185(2):170-181. doi: 10.1159/000534568. Epub 2023 Nov 14.

Abstract

Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by relapsed eczema and serious pruritus. High-mobility group box 1 protein (HMGB1) is a nuclear-binding protein and serves as an alarmin to promote inflammatory responses.

Methods: In this study, we established an AD mouse model by topical use of MC903 on ears and then used a specific HMGB1-binding peptide cIY8 and a HMGB1 inhibitor of glycyrrhizin to investigate HMGB1 on fibroblast activation in the pathogenesis of AD-like symptoms.

Results: Topical use of cIY8 and oral use of glycyrrhizin significantly improved the MC903-induced AD-like symptoms and pathological changes of the ears and scratching behavior in an AD mouse model; cIY8 treatment inhibited the higher mRNAs of IL-1α, IL-4, IL-5, IL-13, and IL-31 in the ears. In human fibroblasts, HMGB1 caused nuclear translocation of NF-kB, and the nuclear translocation could be inhibited by pre-treatment of HMGB1 with cIY8, suggesting that NF-κB signaling pathway participates in the HMGB1-induced inflammation of AD in fibroblasts and that cIY8 effectively impedes the function of HMGB1. Glycyrrhizin inhibited the Ca2+ signaling induced by ionomycin in mouse primary fibroblasts. The fibroblast-related proteins of α-SMA, Hsp47, and vimentin and the pruritus-related proteins of IL-33 and periostin were increased in the ears of the AD mouse model, the ratio of EdU incorporation became higher in mouse fibroblasts treated with MC903, and the higher proliferation and inflammatory responses of the fibroblasts could be reversed by glycyrrhizin treatment.

Conclusions: Fibroblast activation by HMGB1 is one of the critical processes in the development of inflammation and pruritus in the AD mouse model. The specific HMGB1-binding peptide cIY8 and the HMGB1 inhibitor glycyrrhizin inactivate skin fibroblasts to alleviate the inflammation and pruritus in the AD mouse model. Peptide cIY8 may be topically used to treat AD patients in the future.

Keywords: Atopic dermatitis; Fibroblast; HMGB1 antagonist; Inflammation; Pruritus.

MeSH terms

  • Animals
  • Cytokines / metabolism
  • Dermatitis, Atopic* / etiology
  • Glycyrrhizic Acid / adverse effects
  • HMGB1 Protein* / metabolism
  • Humans
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Interleukin-13 / metabolism
  • Mice
  • NF-kappa B / metabolism
  • Pruritus / drug therapy
  • Pruritus / metabolism
  • Skin / pathology

Substances

  • Cytokines
  • Glycyrrhizic Acid
  • HMGB1 Protein
  • Interleukin-13
  • NF-kappa B
  • HMGB1 protein, human
  • HMGB1 protein, mouse

Grants and funding

This work was supported by CIBR Open Cooperation Fund for Science in China (Grant No. 2020-NKX-XM-08 to ZJH) and National Natural Science Foundation of China (Grant No. 81903213 to ZJH). This study also benefitted from the funding of a Joint Sino-German Research Project by the National Natural Science Foundation of China and the DFG (Grant No. GZ901 to ZZT) and the Beijing Municipal Science and Technology Project (Grant No. Z211100007921017 to ZZT).