Butyrate inhibits Staphylococcus aureus-aggravated dermal IL-33 expression and skin inflammation through histone deacetylase inhibition

Atopic dermatitis (AD) is an inflammatory skin disease caused by the disruption of skin barrier, and is dominated by the type 2 immune responses. Patients with AD have a high risk of developing Staphylococcus aureus infection. Interleukin-33 (IL-33), an alarmin, has been implicated in the pathophysiology of AD development. Butyrate, a short chain fatty acid known to be produced from the fermentation of glycerol by the commensal skin bacterium, Staphylococcus epidermidis, has been reported to possess antimicrobial and anti-inflammatory properties that suppress inflammatory dermatoses. However, little is known about the effects of butyrate on dermal IL-33 expression and associated immune response in S. aureus-aggravated skin inflammation in the context of AD. To decipher the underlying mechanism, we established an AD-like mouse model with epidermal barrier disruption by delipidizing the dorsal skin to induce AD-like pathophysiology, followed by the epicutaneous application of S. aureus and butyrate. We discovered that S. aureus infection exacerbated IL-33 release from keratinocytes and aggravated dermal leukocyte infiltration and IL-13 expression. Moreover, we showed that butyrate could attenuate S. aureus-aggravated skin inflammation with decreased IL-33, IL-13, and leukocyte infiltration in the skin. Mechanistically, we demonstrated that butyrate suppressed IL-33 expression and ameliorated skin inflammation through histone deacetylase 3 (HDAC3) inhibition. Overall, our findings revealed the potential positive effect of butyrate in controlling inflammatory skin conditions in AD aggravated by S. aureus infection.

Automated summary

Atopic dermatitis (AD) is an inflammatory skin disease caused by a disrupted skin barrier and dominated by type 2 immune responses. Staphylococcus aureus (S. aureus) infection poses a high risk to patients with AD. Interleukin-33 (IL-33) and butyrate have been implicated in the pathophysiology of AD, but their effects on AD aggravated by S. aureus infection are not well understood. In this study, we established an AD-like mouse model with epidermal barrier disruption and examined the effects of S. aureus and butyrate on IL-33 expression and immune response. We found that S. aureus infection exacerbated IL-33 release and skin inflammation, while butyrate attenuated S. aureus-aggravated skin inflammation through histone deacetylase 3 (HDAC3) inhibition. These findings suggest that butyrate may have a positive effect on controlling inflammatory skin conditions in AD aggravated by S. aureus infection.