Antimicrobial peptides and proteins (AMPs) are a diverse class of naturally occurring molecules that are produced as a first line of defense by all multicellular organisms. These proteins can have broad activity to directly kill bacteria, yeasts, fungi, viruses and even cancer cells. Insects and plants primarily deploy AMPs as an antibiotic to protect against potential pathogenic microbes, but microbes also produce AMPs to defend their environmental niche. In higher eukaryotic organisms, AMPs can also be referred to as 'host defense peptides', emphasizing their additional immunomodulatory activities. These activities are diverse, specific to the type of AMP, and include a variety of cytokine and growth factor-like effects that are relevant to normal immune homeostasis. In some instances, the inappropriate expression of AMPs can also induce autoimmune diseases, thus further highlighting the importance of understanding these molecules and their complex activities. This Primer will provide an update of our current understanding of AMPs.

Adipocytes have been suggested to be immunologically active, but their role in host defense is unclear. We observed rapid proliferation of preadipocytes and expansion of the dermal fat layer after infection of the skin by Staphylococcus aureus. Impaired adipogenesis resulted in increased infection as seen in Zfp423nur12 mice or in mice given inhibitors of peroxisome proliferator–activated receptor γ. This host defense function was mediated through the production of cathelicidin antimicrobial peptide from adipocytes because cathelicidin expression was decreased by inhibition of adipogenesis, and adipocytes from Camp−/− mice lost the capacity to inhibit bacterial growth. Together, these findings show that the production of an antimicrobial peptide by adipocytes is an important element for protection against S. aureus infection of the skin.

The human skin is an organ with a surface area of 1.5-2 m 2 that provides our interface with the environment. The molecular composition of this organ is derived from host cells, microbiota, and external molecules. The chemical makeup of the skin surface is largely undefined. Here we advance the technologies needed to explore the topographical distribution of skin molecules, using 3D mapping of mass spectrometry data and microbial 16S rRNA amplicon sequences. Our 3D maps reveal that the molecular composition of skin has diverse distributions and that the composition is defined not only by skin cells and microbes but also by our daily routines, including the application of hygiene products. The technological development of these maps lays a foundation for studying the spatial relationships of human skin with hygiene, the microbiota, and environment, with potential for developing predictive models of skin phenotypes tailored to individual health.human skin | 3D mapping | mass spectrometry | 16S rRNA T he skin provides the interface between our internal molecular processes and the external environment. The stratum corneum (SC), the outer layer of the epidermis, is the most exposed organ of the human body and is composed of molecules derived from our own skin cells, our microbiota, and the environment (1). In addition, it may be possible that personal hygiene products, the clothing we wear, and the food we eat can affect the chemical composition of the skin (2, 3). The chemical environment of the skin is also critical for the development of microbial communities, yet there are no systematic workflows that can be used to correlate skin chemistry and microbes. Human skin microbiome inventories are changing our views of commensal organisms and their roles in establishing and maintaining the immune system and general epithelial health (4-7), but their role in biotransformation of skin molecules is as yet poorly characterized.Understanding the molecular topography of the surface of the SC will provide insights into the chemical environment in which microbes reside on the skin and how in turn they modify this environment. To understand the relationship between the chemical milieu and the microbial communities, we must develop workflows that map the chemistry and microbiology of the human skin and that determine the associations between them. The composition of the human skin microbiota has been correlated with skin anatomy, dividing into moist, dry, and sebaceous microenvironments, and can be influenced by beauty and hygiene products (2-9). Regions such as the face, chest, and back, areas with a high density of sebaceous glands, promote growth of lipophilic microorganisms such as Propionibacterium and Malassezia. In contrast, less exposed regions, such as the groin, axilla, and toe web, which are higher in temperature and moisture content, are colonized by Staphylococcus and Corynebacterium (7, 10, 11). Previous studies have reported mass spectrometry (MS) methods to identify compounds from human skin (12, 13). However, th...

SUMMARY Type 1 interferons (IFN) promote inflammation in the skin but the mechanisms responsible for inducing these cytokines are not well understood. We found that IFNβ was abundantly produced by epidermal keratinocytes (KCs) in psoriasis and during wound repair. KC IFNβ production depended on stimulation of mitochondrial antiviral-signaling protein (MAVS) by the antimicrobial peptide LL37 and double stranded-RNA released from necrotic cells. MAVS activated downstream TBK1 (TANK-Binding Kinase 1)-AKT (AKT serine/threonine kinase 1)-IRF3 (interferon regulatory factor 3) signaling cascade leading to IFNβ production, and then promoted maturation of dendritic cells. In mice, the production of epidermal IFNβ by LL37 required MAVS, and human wounded and/or psoriatic skin showed activation of MAVS-associated IRF3 and induction of MAVS and IFNβ gene signatures. These findings show that KCs are an important source of IFNβ and MAVS is critical to this function, and demonstrates how the epidermis triggers unwanted skin inflammation under disease conditions.

Epidermal keratinocytes participate in immune defense through their capacity to recognize danger, trigger inflammation, and resist infection. However, normal skin immune function must tolerate contact with an abundant community of commensal microbes without inflammation. We hypothesized that microbial environmental conditions dictate the production of molecules that influence epigenetic events and cause keratinocytes to break innate immune tolerance. , a commensal skin bacterium, produced the short-chain fatty acids (SCFAs) propionate and valerate when provided a lipid source in hypoxic growth conditions, and these SCFAs inhibited histone deacetylase (HDAC) activity. Inhibition of HDAC activity in keratinocytes promoted cytokine expression in response to Toll-like receptor (TLR) ligands for TLR2 or TLR3. This response was opposite to the action of HDAC inhibition on production of inflammatory cytokines by monocytes and involved HDAC8 and HDAC9 because small interfering RNA silencing of these HDACs recapitulated the activity of SCFAs. Analysis of cytokine expression in mice confirmed the response of the epidermis where application of SCFA on the skin surface promoted cytokine expression, whereas subcutaneous administration was inhibitory. These findings show that the products of commensal microbes made under specific conditions will inhibit HDAC activity and break tolerance of the epidermis to inflammatory stimuli.

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Bcl11b is a transcription factor that, within the hematopoietic system, is expressed specifically in T cells. Although Bcl11b is required for T-cell differentiation in newborn Bcl11b-null mice, and for positive selection in the adult thymus of mice bearing a T-celltargeted deletion, the gene network regulated by Bcl11b in T cells is unclear. We report herein that Bcl11b is a bifunctional transcriptional regulator, which is required for the correct expression of approximately 1000 genes in CD4 1 CD8 1 CD3 lo double-positive (DP) thymocytes. Bcl11b-deficient DP cells displayed a gene expression program associated with mature CD4 1 CD8 À and CD4 À CD8 1 single-positive (SP) thymocytes, including upregulation of key transcriptional regulators, such as Zbtb7b and Runx3. Bcl11b interacted with regulatory regions of many dysregulated genes, suggesting a direct role in the transcriptional regulation of these genes. However, inappropriate expression of lineageassociated genes did not result in enhanced differentiation, as deletion of Bcl11b in DP cells prevented development of SP thymocytes, and that of canonical NKT cells. These data establish Bcl11b as a crucial transcriptional regulator in thymocytes, in which Bcl11b functions to prevent the premature expression of genes fundamental to the SP and NKT cell differentiation programs.Key words: Mouse . T-cell differentiation . Transcription factor Supporting Information available online Introduction T-cell differentiation is a complex and dynamic process that leads to the production of functionally distinct populations within the thymus -gd and ab T-cell subsets, the latter of which include helper CD4 1 T cells, cytotoxic CD8 1 T cells, Treg cells, and NKT cells. Hematopoietic progenitor cells enter the thymus as CD4 À CD8 À double-negative (DN) cells and proceed through successive steps of maturation. DN thymocytes are further divided into at least four developmental stages based on the differential expression of CD44 and CD25: CD44 1 CD25 À (DN1), CD44 1 CD25 1 (DN2), CD44 À CD25 1 (DN3), and CD44 À CD25 À Ã Joint senior authors; additional correspondence, Dr. Mark Leid Eur. J. Immunol. 2010. 40: 2143-2154 DOI 10.1002 HIGHLIGHTS 2143Frontline (DN4). gd T cells differentiate from DN3 thymocytes, following rearrangement of the b, g, and d TCR chains. ab T cells develop from DN4 thymocytes that further differentiate into CD4 1 CD8 1 double-positive (DP) CD3 lo abTCR lo thymocytes. Positive selection events between the TCR expressed by DP cells and MHC molecules expressed by thymic stromal cells lead to the appearance of mature CD4 1 and CD8 1 single-positive (SP) CD3 hi /TCR hi thymocytes, and NKT cells, all presumably resulting from large-scale changes in gene expression programs.Transcription factors essential for the ab T-cell developmental programs have been identified [1][2][3]. In particular, Zbtb7b (also known as ThPok) is required for CD4 1 T-cell differentiation [4,5]. Zbtb7b is not expressed in DP thymocytes, but is activated downstream of TCR signaling by TOX [...

Highlights d Neonatal skin is enriched with immature fat and adipogenic dermal fibroblasts d Dermal immature fat and adipogenic-antimicrobial dFBs are lost with age d TGF-b pathway promotes the age-related adipogenic-tofibrotic switch of dFBs d Inhibition of TGFBR restores antimicrobial function of dFBs in adult mice