Editors' Picks

        No more itch

        Treatment of itch has not been as successful as the treatment of pain, and chronic pruritus can be just as debilitating as chronic pain. Our inability to inhibit itch has been due, in part, to our lack of understanding of the underlying neuromodulatory mechanisms. In practice, menthol and other counterstimulatory agents provide almost instantaneous relief of itch, suggesting that crossmodal inhibition occurs centrally, perhaps within the spinal dorsal horn. Kardon and colleagues recently characterized B5-1 neurons, which correspond to specific neurochemically defined populations. These cells release κ-opioid dynorphin, which functions locally within the spinal cord to specifically reduce itch. Dynorphin, then, is a key neuromodulator of pruritus. Interestingly, menthol fails to inhibit itch in mice lacking these neurons, suggesting that B5-1 neurons may mediate inhibition of itch by chemical counterstimuli. These findings provide evidence that?-opioids may be an effective therapy for treating a broad spectrum of chronic itch. (Neuron 82:573–86, 2014) Selected by E. Lerner

        Getting on my nerves

        Imiquimod induces inflammatory lesions that resemble psoriasis via a response that is mediated by IL-23. Interestingly, clinical reports and studies in mice have indicated that intralesionally administered anesthetics or surgical denervation abrogate sensation as well as inflammation. Riol-Blanco and colleagues recently employed the imiquimod mouse model to demonstrate that TRPV1+ nociceptive sensory neurons drive the inflammatory response in IL-23-mediated psoriasiform skin disease. Dermal dendritic cells were found to be the principal source of imiquimod-induced IL-23, and importantly, more than three quarters of these cells were in direct contact or close proximity to sensory neurons. Thus, dermal nociceptors induce nearby dermal dendritic cells to produce Il-23, which then stimulates γδ T cells to secrete IL-17F and IL-22, leading to recruitment of circulating neutrophils and monocytes and subsequent psoriasiform skin inflammation. These findings reveal new avenues for treatment of inflammatory skin diseases. (Nature 510:157–61, 2014) Selected by E. Lerner

        On a scale of seconds and days

        Although atopic dermatitis and other allergic disease are common, the complexity and interplay of genetic and environmental risk factors have hampered our understanding of the disease process. Epidermal barrier permeability is regulated by the growth and differentiation of different cell types on the order of hours to days, whereas the phenotype of each cell within the epithelium is regulated by local effectors via protein–protein interaction networks on the order of seconds to minutes. Domínguez-Hüttinger and colleagues recently reported an ordinary differential equation model of epithelium function that reflects the regulatory interplay between the two different protective properties, which function on different time scales. This multiscale model predicts that the underlying risk factors for atopic dermatitis are predictable from the clinically observed dynamic response of the skin barrier to environmental challenges. This modeling approach allows for the bidirectional interplay between skin barrier dysfunction and aberrant inflammatory response and may contribute directly to development of patient-specific treatment of atopic diseases. (Interface Focus 3:20120090, 2013) Selected by H. Williams

        STING operation

        Nucleic acid sensing is a hallmark of the innate immune response. Indeed, the mere presence of free cytosolic DNA serves as a molecular indicator of danger. Gehrke and colleagues recently found that oxidation-induced DNA structural changes confer resistance to exonuclease TREX1-mediated degradation, leading to accumulation of oxidized DNA in the cytosol. This DNA, which contains the most frequent natural oxidative base modification, 8-hydroxyguanosine, functioned as a potent agonist for the STING-dependent cytoplasmic DNA-sensing pathway. Such oxidation occurs following antimicrobial reactive oxygen production or absorption of UV light. Immune recognition of this UV-damaged self-DNA in the skin may contribute to UV hypersensitivity and development of lesions in sun-exposed skin in patients with the autoimmune disease cutaneous lupus erythematosus. Together, these findings indicate that oxidized DNA constitutes a prototypic damage-associated molecular pattern involved in the TREX1- and STING-mediated pathway of cytosolic DNA sensing in the defense against pathogens and autoimmunity. (Immunity 39:482–95, 2014) Selected by T. Schwarz

        Rescuing research

        Although the past half century has heralded significant scientific discoveries including the genetic code, genome structure, cell cycle, and cell-signaling pathways, a severe imbalance between the money available for research and the ever-growing scientific community in the United States has developed. In a recent perspective, Alberts and colleagues delineated this troubling situation and outlined some possible remedies. These authors propose that the underlying cause of this malaise is the longstanding, yet inaccurate, assumption that the biomedical research system will expand indefinitely. The following recommendations for change were made: predictable budgets for US funding agencies, alterations in the workforce composition, funding for novel groundbreaking work, improvements in the peer-review process, and changes in governmental policies that currently fuel unsustainable research growth. In any case, these points should ultimately spark future discussion and offer a mechanism for progress toward maximizing the contribution of the United States to the global biomedical research enterprise. (Proc Natl Acad Sci USA 111:5773–77, 2014) Selected by L. Goldsmith