Staphylococcus aureus exacerbates dermal IL-33/ILC2 axis activation through evoking RIPK3/MLKL-mediated necroptosis of dry skin.

Atopic dermatitis (AD) is a persistent skin disease typified by symptoms of dry skin and recurrent eczema. Patients with AD are at heightened risk for Staphylococcus aureus infection. Group 2 innate lymphoid cells (ILC2s) are mainly activated by epithelial cell-derived cytokines IL-33 and involved in the pathogenesis of AD. However, little is known about the effect of skin delipidization on the epithelial cell-derived cytokines and dermal ILC2s in AD. In our study, we investigated the mechanism by which S. aureus infection modulates and exacerbates the pathogenesis of dry skin, leading to type 2 inflammation in the context of innate immunity. In vivo, we found that S. aureus infection aggravated delipidization-induced dermal IL-33 release and dermal ILC2 accumulation, which exacerbated skin inflammation. We also noticed that Il33fl/fl K14cre mice and Tlr2-/- mice exhibited attenuated skin inflammation. In vitro, treatment with necroptosis inhibitors reduced IL-33 release from S. aureus-infected keratinocytes. Mechanistically, we observed an increase in the necroptosis-associated kinases, MLKL and RIPK3, in S. aureus-infected mice, indicating that IL-33 release was associated with necroptotic cell death responses. Our results reveal that S. aureus infection-elicited keratinocyte necroptosis contributes to IL-33-mediated type 2 inflammation, which exacerbates the pathogenesis of dry skin.

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.

Immunomodulatory Role of Staphylococcus aureus in Atopic Dermatitis.

Staphylococcus aureus is a gram-positive bacterium commonly found on humans, and it constitutes the skin microbiota. Presence of S. aureus in healthy individuals usually does not pose any threat, as the human body is equipped with many mechanisms to prevent pathogen invasion and infection. However, colonization of S. aureus has been correlated with many healthcare-associated infections, and has been found in people with atopic diseases. In atopic dermatitis, constant fluctuations due to inflammation of the epidermal and mucosal barriers can cause structural changes and allow foreign antigens and pathogens to bypass the first line of defense of the innate system. As they persist, S. aureus can secrete various virulence factors to enhance their survival by host invasion and evasion mechanisms. In response, epithelial cells can release damage-associated molecular patterns, or alarmins such as TSLP, IL-25, IL-33, and chemokines, to recruit innate and adaptive immune cells to cause inflammation. Until recently, IL-36 had been found to play an important role in modulating atopic dermatitis. Secretion of IL-36 from keratinocytes can activate a Th2 independent pathway to trigger symptoms of allergic reaction resulting in clinical manifestations. This mini review aims to summarize the immunomodulatory roles of S. aureus virulence factors and how they contribute to the pathogenesis of atopic diseases.