HDAC6 and CXCL13 Mediate Atopic Dermatitis by Regulating Cellular Interactions and Expression Levels of miR-9 and SIRT1

Abstract

Histone deacetylase 6 (HDAC6) has been known to regulate inflammatory diseases. The role of HDAC6 in allergic skin inflammation has not been studied. We studied the role of HDAC6 in atopic dermatitis (AD) and the mechanisms associated with it. The decreased expression or chemical inhibition of HDAC6 suppressed AD by decreasing autophagic flux and cellular features of AD. AD increased expression levels of the Th1 and Th2 cytokines, but decreased expression levels of forkhead box P3 (FoxP3) and interleukin-10 (IL-10) in an HDAC6-dependent manner. CXC chemokine ligand 13 (CXCL13), which was increased in an HDAC6-depenednt manner, mediated AD. MiR-9, negatively regulated by HDAC6, suppressed AD by directly regulating the expression of sirtuin 1 (SIRT1). The downregulation or inhibition of SIRT1 suppressed AD. Experiments employing culture medium and transwell suggested that cellular interactions involving mast cells, keratinocytes, and dermal fibroblast cells could promote AD; HDAC6 and CXCL13 were found to be necessary for these cellular interactions. Mouse recombinant CXCL13 protein increased HDAC6 expression in skin mast cells and dermal fibroblast cells. CXCL13 protein was found to be present in the exosomes of DNCB-treated skin mast cells. Exosomes of DNCB-treated skin mast cells enhanced invasion potentials of keratinocytes and dermal fibroblast cells and increased expression levels of HDAC6, SIRT1 and CXCL13 in keratinocytes and dermal fibroblast cells. These results indicate that HDAC6 and CXCL13 may serve as targets for the developing anti-atopic drugs.

Identification of exosome-related gene signature as a promising diagnostic and therapeutic tool for breast cancer

“…Recent studies have shown that PIGR can serve as a biomarker for good outcomes in luminal breast cancer [ 73 ], and the current study suggests that high PIGR expression is associated with better survival. CXCL13 has been identified as a key mediator of cellular interactions and a hallmark of allergic inflammation, as reported in previous studies [ 74 ]. The CXCL13 gene encodes chemokine 13 (C-X-C motif chemokine ligand 13) and is expressed in lymphoid tissue, playing a significant role in immune regulation, especially in lymph node formation and B-cell attraction [ 75 ].…”

HDAC6 inhibition alleviates acute pulmonary embolism: a possible future therapeutic option

“…HDAC6 is a microtubule-associated deacetylase that regulates post-translational modification and in this way may modulate gene expression. HDAC6 has been reported to be involved in a variety of inflammatory diseases, such as myocarditis and cardiac dysfunction [34], rheumatoid arthritis [35], atopic dermatitis [36], and other diseases. As a special member of HDAC enzymes, HDAC6 also plays a vital role in other physiological functions.…”

The role of dermal fibroblasts in autoimmune skin diseases

“…The degradation of the skin barrier is the direct cause of AD. Kwon indicated that HDAC6 and CXCL13 were increased in AD fibroblasts and enhanced cellular interactions between mast cells, keratinocytes, leading to impaired skin barrier function ( 44 ). Research showed that IL-22 increased in the skin and blood of AD patients, and the elevated IL-22 concentrations are highly correlated with skin barrier defects ( 41 ).…”