Montagna Symposium 2010: small molecules: skin as the first line of defense.

The 2010 Montagna Symposium, Small Molecules: Skin as the First Line of Defense,* was attended by approximately 100 scientists, clinicians, residents, students, industrial representatives, and National Institutes of Health (NIH) representatives. The three-day program comprised five sessions: (i) “Science-Driven Therapeutics,” (ii) “Host Defense Peptides,” (iii) “Neuroendocrine Functions in Skin,” (iv) “Small Molecules of the Skin Barrier,” and (v) “Skin Defense Strategies.” Two important goals of the meeting were to explore the skin’s innate ability to protect itself via small molecules and to determine how scientists and clinicians might enhance this ability. The sessions were organized to reflect these goals, beginning with known defensive strategies, moving through recent small-molecule discoveries, and, finally, addressing how to generate new potential strategies. In addition to invited speakers, several people were selected to give short talks based on abstract submissions. As in years past, discussion after each talk was productive and lively. Michael Zasloff (Georgetown University, Washington, DC) opened the meeting with a keynote address describing wound healing in dolphins, which occurs without infection or an immune infiltrate. Dr. Zasloff explained that wounds are closed by the blubber layer below, which billows upward, resulting in an increase in antimicrobials over the wound. The dolphins appear to have no pain associated with the wounds. Dr. Zasloff suggested that this is attributable to the blubber’s anti-inflammatory and antimicrobial activity. The goal of the first full session, “Science-Driven Therapeutics,” was to explore the role of basic science in the discovery of novel therapies. Barbara Gilchrest (Boston University, Massachusetts) began the session by describing the discovery of small telomeric oligos that could induce the tanning response and might therefore be a good therapy for preventing UV-induced skin cancer. She is currently working on the problem of penetration of the oligos through the human skin barrier. Two talks discussed the skin as a neurosensory organ. Peter Elias (San Francisco VA Medical Center, California) described how psychological stress induces the production of small molecules, such as β-defensins, cathelicidin protein, and the neuroendocrine peptide catestatin, which are necessary during the initial inflammatory response of wound healing but become deleterious to barrier function once inflammation resides. Richard Granstein (Weill–Cornell Medical Center, New York) discussed the skin’s production of calcitonin gene–related peptide (CGRP), a neuropeptide, and its direct anti- and proinflammatory effects on endothelial cells in the dermis. Xiao-Jing Wang (University of Colorado, Denver) described her yin–yang approach to understanding the conundrum of how transforming growth factor-β1, which suppresses the immune system, can induce psoriasis, which is caused by an increase in the inflammatory response of T lymphocytes. William Fenical (Scripps Institute of Oceanography, University of California, San Diego) discussed the lack of immune response in ocean-dwelling creatures. He suggested that sea shrimp eggs and their bacterial symbiotic relationship to produce antibiotic peptides against invading bacteria might parallel the microbe–tissue associations in human skin. The discussion of inflammation and the microbiome of skin was continued in the second session, “Host Defense Peptides,” by Jens-Michael Schroeder (University of Kiel, Germany) and Michel Gilliet (University of Texas M.D. Anderson Cancer Center, Houston). Dr. Schroeder explained that skin has a high level of natural bacteria, but that invading bacteria induce the skin to produce high levels of antimicrobial peptides. Dr. Gilliet followed with evidence that the induced antimicrobial peptides trigger activation of plasmacytoid dendritic cells and that miscontrol of this process might lead to psoriasis. Jamie Bernard (University of California, San Diego), a Farber Travel Award Winner, explained that Cox-2 is required to enhance the antimicrobial peptide expression in keratinocytes. Andrew Johnston (University of Michigan, Ann Arbor) reported that IL-1 family members, which induce antimicrobial peptides in skin, are inhibited by psoriatic treatments. The third scientific session, “Neuroendocrine Functions in Skin,” explored the relationship between neuroendocrine function and antimicrobial activity of the skin. Martin Steinhoff (University of California, San Francisco) began the session with an overview of the skin as a neuro-immune organ. He explained that the skin is the first line of immune and sensory detection, sending danger signals to the brain. Katherine Raek (Loyola University, Chicago, Illinois) described a study in which stress activated the nicotinic receptors in skin keratinocytes, resulting in a reduction of cutaneous antimicrobial activity. Stephen Ostrowski (Case Western Reserve University, Cleveland, Ohio), a Farber Travel Award winner, explained that nerve-derived substance P and CGRP help sustain cutaneous cell infiltration and contribute to acanthosis. Daniel Bikle (University of California, San Francisco) gave a general overview of the nonclassic functions of vitamin D and the vitamin D receptor. He emphasized that cell types that make their own vitamin D appear to be able to ward off infection. This was followed by short talks from two Farber Travel Award Winners. Jose Fernandez (Signum Biosciences, Monmouth, New Jersey) discussed safety issues involved with topical antimicrobial treatments, and Ferda Cevikbas (University of California, San Francisco) described how IL-31 results in increased scratching and CGRP release. In the fourth session, “Small Molecules of the Skin Barrier,” Thomas Luger (University of Munster, Germany) further explored the role of neuropeptides in mediating inflammation and the innate defense of the skin as a barrier. Robert Hancock (University of British Columbia, Vancouver, Canada) outlined his technique for rapidly building and testing small molecules and their ability to boost the skin’s innate immunity. Luowei Li (National Cancer Institute (NCI), NIH, Bethesda, Maryland) discussed the necessity of a functioning ABCB1 multidrug transporter to deliver chemotherapeutic agents. Two talks concerning the skin’s microbiome were presented. Heidi Kong (NCI, NIH) described the variability of the bacterial complement across skin from several body sites. She explained that the healthy state is associated with much diversity and emphasized that general destruction of the innate microbiome is associated with disease. Richard Gallo (University of California, San Diego) continued this theme, explaining how the host microbiome contributes to the host defense through production of antimicrobial peptides that fight invading microbes. Stephanie Shirley (University of Texas M.D. Anderson Cancer Center) discussed the role of the transcription factor Slug in producing dimmers of S100 proteins, which are antimicrobial. In the last scientific session, “Skin Defense Strategies,” Richard Eckert (University of Maryland School of Medicine, Baltimore) presented an overview of S100 proteins in the epidermis. He emphasized that specific S100 proteins bound in the cornified cell envelope are released upon bacterial invasion and that these S100 proteins can kill Escherichia coli but do not kill Staphylococcus aureus. Adrian Gombert (Linus Pauling Institute, Oregon State University, Corvallis) described his mouse model, which contains a primate-specific, vitamin D–regulated cathelicidin antimicrobial peptide. Ronald Wolf, a Farber Travel Award winner (Ludwig Maximilian University, Munich, Germany), ended the session with a discussion of a mouse model that in basal keratinocytes overexpresses the S100A7 and S100A15 genes, two peptides highly expressed in psoriasis. The meeting ended with an overall discussion session entitled “Translation to Treatment: What’s the Next Step?”