Human skin and its immune cells provide essential protection of the human body from injury and infection. Recent studies reinforce the importance of keratinocytes as sensors of danger through alert systems such as the inflammasome. In addition, newly identified CD103 + dendritic cells are strategically positioned for cross-presentation of skin-tropic pathogens and accumulating data highlight a key role of tissue-resident rather than circulating T cells in skin homeostasis and pathology. This Review focuses on recent progress in dissecting the functional role of skin immune cells in skin disease.The skin, as the primary interface between the body and the environment, provides a first line of defence against microbial pathogens and physical and chemical insults. Immunosurveillance of such a large and exposed organ presents unique challenges for immune sentinels and effector cells. If an immune response is inadequate then overwhelming infections or tumours may ensue, but if an immune response is excessive then chronic inflammation and autoimmunity may develop. Controlling the extent of an immune response is thus a major challenge for maintaining skin integrity, which is of paramount importance for host survival. Therefore, both active defence mechanisms and tolerogenic pathways are used by the host to achieve immune homeostasis, ensuring that immune responses in the skin are properly adjusted to various challenges.Owing to its accessibility, the skin is an ideal organ system in which to study both tissue and whole-organism responses to local and systemic insults. A growing body of data supports the notion that the skin has essential immunological functions, both during tissue homeostasis and in various pathological conditions. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptAlthough early studies highlighted individual cell types in the skin, it was the visionary concept of the skin-associated lymphoid tissue (SALT), first described by Streilein in 1983 (REF. 1 ), and later the 'skin immune system' (REF. 2 ) that provided a modern interpretation and overall paradigm for investigators interested in cutaneous immunology. The initial SALT concept introduced the idea of distinct circuiting immune cells that continually traffic in a directed manner between the skin, the draining lymph nodes and the circulation, thereby providing optimal immunosurveillance.Although considerable attention was directed at the function of epidermal Langerhans cells 3 , it became apparent that other types of dendritic cells (DCs) and innate immune cells present in the dermis also have a relevant role, resulting in the emergence of the concept of a 'dermal immune system' (REF. 4 ). Human skin has two main compartments: the epidermis and the dermis (FIG. 1). The epidermis is the outer compartment and contains four strata. The stratum basale is the bottom layer of the epidermis and is responsible for constantly renewing the cells of the epidermis. This layer contains just one row of undifferentiated epidermal ...

No abstract

Here we report that epidermal keratinocytes in psoriatic lesions are characterized by activated Stat3. Transgenic mice with keratinocytes expressing a constitutively active Stat3 (K5.Stat3C mice) develop a skin phenotype either spontaneously, or in response to wounding, that closely resembles psoriasis. Keratinocytes from K5.Stat3C mice show upregulation of several molecules linked to the pathogenesis of psoriasis. In addition, the development of psoriatic lesions in K5.Stat3C mice requires cooperation between Stat3 activation in keratinocytes and activated T cells. Finally, abrogation of Stat3 function by a decoy oligonucleotide inhibits the onset and reverses established psoriatic lesions in K5.Stat3C mice. Thus, targeting Stat3 may be potentially therapeutic in the treatment of psoriasis.

Bidirectional cellular communication is integral to both cancer progression and embryological development. In addition, aggressive tumor cells are phenotypically plastic, sharing many properties with embryonic cells. Owing to the similarities between these two types of cells, the developing zebrafish can be used as a biosensor for tumor-derived signals. Using this system, we show that aggressive melanoma cells secrete Nodal (a potent embryonic morphogen) and consequently can induce ectopic formation of the embryonic axis. We further show that Nodal is present in human metastatic tumors, but not in normal skin, and thus may be involved in melanoma pathogenesis. Inhibition of Nodal signaling reduces melanoma cell invasiveness, colony formation and tumorigenicity. Nodal inhibition also promotes the reversion of melanoma cells toward a melanocytic phenotype. These data suggest that Nodal signaling has a key role in melanoma cell plasticity and tumorigenicity, thereby providing a previously unknown molecular target for regulating tumor progression.