HMGB1-mediated chromatin remodeling attenuates Il24 gene expression for the protection from allergic contact dermatitis

Abstract

Dysregulation of inflammatory cytokines in keratinocytes promote the pathogenesis of the skin inflammation, such as allergic contact dermatitis (ACD). High-mobility group box 1 protein (HMGB1) has been implicated in the promotion of skin inflammation upon its extracellular release as a damage-associated molecular pattern molecule. However, whether and how HMGB1 in keratinocytes contributes to ACD and other skin disorders remain elusive. In this study, we generated conditional knockout mice in which theHmgb1gene is specifically deleted in keratinocytes, and examined its role in ACD models. Interestingly, the mutant mice showed exacerbated skin inflammation, accompanied by increased ear thickening in 2,4-dinitrofluorobenezene-induced ACDs. The mRNA expression of interleukin-24 (IL-24), a cytokine known to critically contribute to ACD pathogenesis, was elevated in skin lesions of the mutant mice. As with constitutively expressed, IL-4–inducedIl24mRNA, expression was also augmented in theHmgb1-deficient keratinocytes, which would account for the exacerbation of ACD in the mutant mice. Mechanistically, we observed an increased binding of trimethyl histone H3 (lys4) (H3K4me3), a hallmark of transcriptionally active genes, to the promoter region of theIl24gene in thehmgb1-deficient cells. Thus, the nuclear HMGB1 is a critical “gate keeper” in that the dermal homeostasis is contingent to its function in chromatin remodeling. Our study revealed a facet of nuclear HMGB1, namely its antiinflammatory function in keratinocytes for the skin homeostasis.

Reduced HMGB1 expression contributed to lapatinib-induced cutaneous injury

“…In addition to the well-known function as an inflammatory cytokine after release, intranuclear HMGB1 is of significance in regulating gene transcription, DNA damage repair, chromatin remodeling and stabilizing nucleosome structure (Kang et al, 2014). Abundant evidence supports that nuclear HMGB1 is essential for maintaining skin homeostasis (Senda et al, 2021). Thus, we envisaged that decreased HMGB1 expression might be the key event in lapatinib-induced cutaneous toxicity.…”

“…Decreased epidermal content of HMGB1 has been identified in drug-induced SJS/TEN, raising the possibility that the analysis of HMGB1 in keratinocytes may represent a potential diagnostic marker of cell death/tissue damage in SJS/TEN (Carr et al, 2019). In addition, studies have provided evidence to support the notion that HMGB1 function to attenuate the expression of interleukin-24 (IL24) by chromatin remodeling, thereby protecting against dermatitis (Senda et al, 2021). These findings above have underscored the unprecedented function of HMGB1 in skin disorders, however, the precise mechanism underlying HMGB1 mediating the drug-induced skin injury has yet to be clarified.…”

Potential skin health promoting benefits of costunolide: a therapeutic strategy to improve skin inflammation in imiquimod-induced psoriasis

“…It is widely present in the nucleus, cytoplasm and cytoplasmic matrix, and the inflammatory response and immune function mediated by HMGB1 also play a role in skin-related diseases. 11,12…”

Nuclear HMGB1 protects from nonalcoholic fatty liver disease through negative regulation of liver X receptor

“…A very recent report depicts nuclear HMGB1 as an even more versatile factor able to bind to topologically associated domains or RNA directly to regulate proliferation or senescence programs ( 31 ). In cultured cells, while HMGB1 deletion leads to minor changes in histone numbers, it results in notable changes of the RNA pool ( 27 ), in local chromatin remodeling ( 32 ) or the global transcriptome ( 31 ). However, only a sparse number of studies have been carried out in vivo ( 32 ).…”

“…In cultured cells, while HMGB1 deletion leads to minor changes in histone numbers, it results in notable changes of the RNA pool ( 27 ), in local chromatin remodeling ( 32 ) or the global transcriptome ( 31 ). However, only a sparse number of studies have been carried out in vivo ( 32 ). The global ablation of Hmgb1 generates a severe phenotype with perinatal mortality ( 33 ), likely due to a defective glucocorticoid signaling leading to a poor utilization of hepatic glycogen and resulting in a lethal hypoglycemia, whereas hepatocyte-specific HMGB1 ablation did not have a major impact under homeostatic conditions ( 34 ).…”