Changes in Bacteria Induce Inflammatory Skin Diseases
The role of dysbiosis in the pathogenesis of atopic dermatitis has been unclear. Nagao and colleagues study mice with eczematous dermatitis and naturally occurring dysbiosis and demonstrate that eczematous dermatitis is driven by S. aureus and T helper 2 responses are enhanced by Corynebacterium bovis. Dysbiosis occurred in part dependent on EGFR signaling.
Atopic dermatitis (AD) is a chronic inflammatory skin disease that manifests as dry skin with a relentless itch and eczema. AD is considered an allergic disease in which the skin inflammation manifests in response to chronic exposure to contact allergens. However, identification of a responsible allergen is uncommon. Meanwhile, analyses have demonstrated that the surface of the human body is colonized by large numbers of diverse bacteria. This observation has led researchers to examine the roles these bacteria play in healthy and diseased skin. In a variety of genetic and chronic inflammatory skin diseases, including in patients with AD or with cancer who receive epidermal growth factor receptor (EGFR) inhibitors, Staphylococcus aureus and Corynebacterium species are the predominant bacteria isolated from the skin. However, the cause-and-effect relationship between this microbial imbalance and skin inflammation has not been determined.
One recently-identified genetic disorder that leads to skin inflammation is a deficiency in a disintigrin and metalloproteinase 17 (ADAM17), which converts pro-tumor necrosis factor α and pro-EGFR ligands into their active forms. Keisuke (Chris) Nagao, M.D., Ph.D., of CCR’s Dermatology Branch, and his colleagues had generated mice lacking the ADAM17 gene in Sox9-expressing tissues, which include the skin, because they were studying its function in bones and hair follicles. The investigators found that these mice, like their human counterparts, developed dry skin that progressed to eczema with intense itching, suggesting they may serve as a model of chronic inflammatory skin diseases, such as AD. Biopsies of the skin lesions revealed infiltration of lymphocytes and mast cells. Further studies showed barrier dysfunction and elevated serum IgE levels in the transgenic mice. Likewise, T helper 1 (Th1) and Th2 cell numbers in skin draining lymph nodes increased, and the composition of epidermal T cells changed significantly. Because these phenotypes mimic symptoms observed in patients, the scientists decided to examine the surface bacteria of ADAM17ΔSox9 mice.
The researchers swabbed the skin of eight week old ADAM17ΔSox9 mice and wild type littermates and cultured the bacteria present. There was a significant outgrowth of S. aureus from the ADAM17ΔSox9 but not the wild type cultures. To further characterize the skin microbiota, the investigators performed bacterial 16S rRNA sequencing on samples from wild type and ADAM17ΔSox9 mice between two and 14 weeks after birth. At two weeks, the microbiota of wild type and ADAM17ΔSox9 mice were indistinguishable. However, dramatic changes in the ADAM17ΔSox9 microbiota occurred at weeks three and four, which included the emergence of Corynebacterium mastitidis. Increased S. aureus was observed at week six and coincided with aggravated skin symptoms. After the emergence of S. aureus, C. mastitidis disappeared and was replaced by Corynebacterium bovis. These bacterial imbalances on the skin of the ADAM17ΔSox9 mice recapitulated the changes seen in human disease.
To see whether the bacterial imbalance caused skin inflammation, the scientists treated one group of ADAM17ΔSox9 mice with the antibiotics cefazolin and enrofloxacin and left another group untreated. Mice that received antibiotics were almost completely protected from skin lesions. Similarly, the barrier function improved, and serum IgE levels went down. The number of T helper cells fell, and the epidermal T cell composition normalized. The researchers observed higher bacterial diversity in the antibiotic-treated mice as well a decrease in the proportions of S. aureus and C. bovis. They next performed crossover studies where one group of ADAM17ΔSox9 mice were untreated through week 10 after birth and then received antibiotics while another group was treated between weeks three and 10 and then treatment stopped. Encouragingly, starting antibiotics in initially untreated mice reversed skin inflammation and bacterial imbalance, suggesting that targeting the imbalance was therapeutic. Conversely, withdrawing antibiotics enhanced skin inflammation and led to the emergence of S. aureus and C. bovis. When the investigators examined the contribution of each bacterial species to the inflammatory phenotype, they found that S. aureus was mainly responsible for inducing dermatitis while C. bovis predominantly enhanced Th2 responses that are expected to elevate IgE. Investigating the contribution of various immune cells revealed that Langerhans cells, special dendritic cells in the skin, mediated innate responses to S. aureus.
ADAM17 functions upstream of EGFR signaling, which has been implicated in skin immune homeostasis. To evaluate the contribution of EGFR signaling to microbial imbalance and skin inflammation, the scientists generated a mouse line lacking the EGFR gene in Sox9-expressing cells. The EGFRΔSox9 mice developed eczema similar to, though slightly less severe than, the ADAM17ΔSox9 mice. Likewise, the EGFRΔSox9 mice showed reduced barrier function, elevated serum IgE, and changes in inflammatory cell numbers. Loss of EGFR signaling in the skin also led to microbial imbalance with an emergence of S. aureus and Corynebacterium species. Thus, ADAM17 regulates the skin microbiome in an EGFR-dependent manner.
Together, these studies demonstrate that S. aureus is a critical component of eczema formation. While these results need to be validated in humans, they provide the impetus for the development of novel therapeutic strategies that target specific aspects of chronic skin inflammation, such as those that initiate bacterial imbalances and trigger immune responses downstream of the bacteria, as well as the bacteria themselves.Summary Posted: Fri, 05/01/2015
Kobayashi T, Glatz M, Horiuchi K, Kawasaki H, Akiyama H, Kaplan DH, Kong HH, Amagai M, and Nagao K. Dysbiosis and Staphylococcus aureus colonization drives inflammation in atopic dermatitis. Immunity. April 21, 2015 PubMed Link