The many influences of retinoic acid
Transforming growth factor-
(TGF-) drives the differentiation of regulatory T (Treg) cells, yet also results in the differentiation of T helper-17 (TH17) cells in the presence of interleukin-6. These seemingly opposing roles of this cytokine prompted Mucida and colleagues to investigate the mechanisms of differentiation. Retinoic acid (RA), which is derived from dendritic cells, opposed TH17 cell differentiation both in cell culture and in mouse models via a direct effect on the orphan nuclear receptor ROR
t. In contrast, RA induced the differentiation of Treg cells. Thus, RA controls the reciprocal differentiation of the TGF--dependent Treg and TH17 immune cells. In a mouse model of colitis, the Foxp3+ Treg cells generated by RA and TGF- treatment effectively controlled inflammation. Therefore, understanding the regulation of the proinflammatory and anti-inflammatory T cells by TGF- may be critical for influencing immunopathophysiology. (Science 317:256–60, 2007)
Atomic view of lipid recognition
The CD1 molecules are major histocompatibility complex (MHC) class I–like glycoproteins that present lipid antigens to T cells. Natural killer T (NKT) cells express a semivariant T-cell receptor (TCR) that interacts with CD1d molecules presenting self or foreign lipid antigens. Despite the extensive research on the TCR–peptide–MHC interactions, the nature of the TCR interaction with CD1 molecules is obscure. Recently, Borg and colleagues determined the crystal structure of the NKT TCR–CD1d complex with 
-galactosylceramide, the prototypical NKT-cell antigen. Interestingly, the NKT TCR adopted an acute docking mode at the extreme end of the CD1d–antigen binding cleft and in parallel to the long axis of the CD1d–antigen binding cleft. These binding features are in direct contrast with MHC class I–peptide-TCR footprints. NKT cells bridge the innate and adaptive immune responses, and thus the structure of this complex offers information for the design of modulators of both NKT-cell functions. (Nature 448:44–8, 2007)
Sound the alarmins for rosacea
The term "alarmins" has been used to describe antimicrobial peptides such as defensins and cathelicidins, which not only kill microbes but also trigger host-tissue responses, including leukocyte chemotaxis, angiogenesis, expression of extracellular matrix components, and inflammation. Rosacea, an inflammatory skin disease, exhibits many of these resultant characteristics. Thus, Yamasaki and colleagues recently identified altered levels and post-translational processing of cathelicidin in skin from rosacea patients. When cultured with human keratinocytes, abnormal cathelicidin peptides resulted in erythema and vascular dilatation. Deletion of the cathelicidin gene in a mouse model of skin irritation resulted in significantly less inflammation than in wild-type animals. In addition, increases in the activity of serine proteases that lead to activation of cathelicidin were implicated in inflammatory changes associated with rosacea. Thus, manipulation of antimicrobial peptides and their postsecretory processing may be a focus for the development of effective therapeutic strategies for rosacea. (Nat Med 13:975–80, 2007)
Itch straight from the spine
Although chronic itch is a significant clinical problem that results from renal and liver diseases as well as from skin disorders such as atopic dermatitis, the itch-specific mediator in the central nervous system has not yet been identified. Sun and Chen, however, recently identified the gastrin-releasing peptide receptor (GRPR) as a critical component of pruritus. GRPR mutant mice and wild-type mice exhibited similar responses to thermal, mechanical, inflammatory, and neuropathic pain sensations. Following treatment with pruritogenic agents such as a mast-cell degranulation compound (48/80), a histamine-independent itch inducer (SLIGRL-NH2), and chloroquine, the mutant mice displayed significantly reduced scratching behaviors compared with the treated wild-type mice. Intriguingly, intrathecal administration of a GRPR agonist induced scratching behavior in a dose-dependent manner, whereas subsequent intrathecal injection of a GRPR antagonist inhibited this scratching. Together, these data support the notion that GRP functions via the spinal GRPR to transmit signals to instigate scratching behavior following pruritogenic stimuli but not following noxious stimuli. (Nature 448:700–3, 2007)
Keeping water in and radiation out
Denecker and colleagues examined caspase-14-deficient mice to explore the role of caspase-14 in terminal keratinocyte differentiation and cornification. Although no covert abnormalities in skin structure, survival, or growth were noted, these mice were shinier and more lichenified than the wild-type mice. The stratum corneum, where caspase-14 is proteolytically activated, demonstrated no histological abnormalities in the mutant animals; however, scanning microscopic analysis revealed larger scales in the mutant mice. Filaggrin accumulated in the upper layers of the stratum corneum, and the profillagrin pattern was altered in the caspase-14-deficient mice. These mutant mice demonstrated an increased transepidermal water loss and a decreased stratum corneum hydration level. Finally, the caspase-14-deficient mice exhibited significantly more epidermal cellular damage and greater DNA damage in the form of cyclobutane pyrimidine dimers following exposure to UVB radiation. These results illuminate caspase-14 as essential for epidermal barrier function in water-loss prevention and protection from irradiation. (Nat Cell Biol 9:666–74, 2007)
