Beneficial effects of coagulase-negative Staphylococci on Staphylococcus aureus skin colonization.

Our skin is constantly exposed to a large number of pathogens while at the same time undergoing selective colonization by commensal microorganisms such as coagulase-negative Staphylococci. Staphylococcus aureus, however, is a facultative pathogen that is usually absent from healthy skin but frequently colonizes the inflamed skin of atopic dermatitis patients, where it further promotes inflammation. Enhanced S. aureus skin colonization was shown to correlate with a loss of microbiome diversity indicating a role for skin commensals to shape pathogen colonization. Together, keratinocytes and immune cells in the skin need to discriminate commensals from pathogens and orchestrate subsequent immune reactions in response to colonizing microbes. However, the mechanisms how individual commensals cooperate with keratinocytes and the immune system of the skin to prevent pathogen colonization are barely understood. In this review, we discuss the current knowledge on the functional effects of coagulase-negative staphylococci, the most frequently isolated skin commensals, on S. aureus skin colonization.

IL-26 Potentiates Type 2 Skin Inflammation in the Presence of IL-1ß.

Atopic dermatitis (AD) is a debilitating inflammatory skin disorder. Biologics targeting the IL-4/IL-13 axis are effective in AD, but there is still a large proportion of patients who do not respond to IL-4R blockade. Further exploration of potentially pathogenic T-cell-derived cytokines in AD may lead to new effective treatments. This study aimed to investigate the downstream effects of IL-26 on skin in the context of type 2 skin inflammation. We found that IL-26 alone exhibited limited inflammatory activity in the skin. However, in the presence of IL-1ß, IL-26 potentiated the secretion of TSLP, CXCL1, and CCL20 from human epidermis through Jak/signal transducer and activator of transcription signaling. Moreover, in an in vivo AD-like skin inflammation model, IL-26 exacerbated skin pathology and locally increased type 2 cytokines, most notably of IL13 in skin T helper cells. Neutralization of IL-1ß abrogated IL-26-mediated effects, indicating that the presence of IL-1ß is required for full IL-26 downstream action in vivo. These findings suggest that the presence of IL-1ß enables IL-26 to be a key amplifier of inflammation in the skin. As such, IL-26 may contribute to the development and pathogenesis of inflammatory skin disorders such as AD.

IL-17 Signaling in Keratinocytes Orchestrates the Defense against Staphylococcus aureus Skin Infection.

Keratinocytes (KCs) form the outer epithelial barrier of the body, protecting against invading pathogens. Mice lacking the IL-17RA or both IL-17A and IL-17F develop spontaneous Staphylococcusaureus skin infections. We found a marked expansion of T17 cells, comprised of RORγt-expressing γδ T cells and T helper 17 cells in the skin-draining lymph nodes of these mice. Contradictory to previous suggestions, this expansion was not a result of a direct negative feedback loop because we found no expansion of T17 cells in mice lacking IL-17 signaling specifically in T cells. Instead, we found that the T17 expansion depended on the microbiota and was observed only when KCs were deficient for IL-17RA signaling. Indeed, mice that lack IL-17RA only in KCs showed an increased susceptibility to experimental epicutaneous infection with S. aureus together with an accumulation of IL-17A-producing γδ T cells. We conclude that deficiency of IL-17RA on KCs leads to microbiota dysbiosis in the skin, which triggers the expansion of IL-17A-producing T cells. Our data show that KCs are the primary target cells of IL-17A and IL-17F, coordinating the defense against microbial invaders in the skin.