Neuroendocrine Controls of Keratin Expression in Human Skin

The human skin serves as a source for a large number of neurohormones and neuropeptides, which affect skin biology on multiple different levels. Intriguingly, this includes the control of keratin expression by neurohormones such as thyrotropin-releasing hormone, thyrotropin, opioids, prolactin, and cannabinoid receptor 1-ligands. While this neuroendocrine regulation of human keratin biology in situ is likely to be involved in the maintenance of skin and hair follicle homeostasis and may participate in skin pathology, this regulation remains to be appreciated and explored by mainstream keratin research. Here, we review recent progress in this frontier of neuroendocrine and keratin skin research, define the many open questions in the field, and elaborate how neurohormones may be harnessed to treat selected genodermatoses and other skin disorders accompanied by abnormal keratin expression

A novel control of human keratin expression: cannabinoid receptor 1-mediated signaling down-regulates the expression of keratins K6 and K16 in human keratinocytes in vitro and in situ

Cannabinoid receptors (CB) are expressed throughout human skin epithelium. CB1 activation inhibits human hair growth and decreases proliferation of epidermal keratinocytes. Since psoriasis is a chronic hyperproliferative, inflammatory skin disease, it is conceivable that the therapeutic modulation of CB signaling, which can inhibit both proliferation and inflammation, could win a place in future psoriasis management. Given that psoriasis is characterized by up-regulation of keratins K6 and K16, we have investigated whether CB1 stimulation modulates their expression in human epidermis. Treatment of organ-cultured human skin with the CB1-specific agonist, arachidonoyl-chloro-ethanolamide (ACEA), decreased K6 and K16 staining intensity in situ. At the gene and protein levels, ACEA also decreased K6 expression of cultured HaCaT keratinocytes, which show some similarities to psoriatic keratinocytes. These effects were partly antagonized by the CB1-specific antagonist, AM251. While CB1-mediated signaling also significantly inhibited human epidermal keratinocyte proliferation in situ, as shown by K6/Ki-67-double immunofluorescence, the inhibitory effect of ACEA on K6 expression in situ was independent of its anti-proliferative effect. Given recent appreciation of the role of K6 as a functionally important protein that regulates epithelial wound healing in mice, it is conceivable that the novel CB1-mediated regulation of keratin 6/16 revealed here also is relevant to wound healing. Taken together, our results suggest that cannabinoids and their receptors constitute a novel, clinically relevant control element of human K6 and K16 expression

The histological and immunohistochemical features of the skin lesions in CANDLE syndrome

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is a newly characterized autoinflammatory disorder, caused by mutations in PSMB8. It is characterized by early-onset fevers, accompanied by a widespread, violaceous and often annular, cutaneous eruption. While the exact pathogenesis of this syndrome is still obscure, it is postulated that the inflammatory disease manifestations stem from excess secretion of interferons. Based on preliminary blood cytokine and gene expression studies, the signature seems to come mostly from type I interferons, which are proposed to lead to the recruitment of immature myeloid cells into the dermis and subcutis. In this study, we systematically analyzed skin biopsies from 6 CANDLE syndrome patients by routine histopathology and immunohistochemistry methods. Skin lesions showed the presence of extensive mixed dermal and subcutaneous inflammatory infiltrate, composed of mononuclear cells, atypical myeloid cells, neutrophils, eosinophils and some mature lymphocytes. Positive LEDER and myeloperoxidase staining supported the presence of myeloid cells. Positive CD68/PMG1 and CD163 staining confirmed the existence of histiocytes and monocytic macrophages in the inflammatory infiltrate. CD123 staining was positive, demonstrating the presence of plasmacytoid dendritic cells. Uncovering the unique histopathologic and immunohistochemical features of CANDLE syndrome provides tools for rapid and specific diagnosis of this disorder as well as further insight into the pathogenesis of this severe, life-threatening conditionThis work was supported in part by the NIAMS Intramural Research Program (IRP) at the National Institutes of Health (NIH); The Authority for Research and Development, Hebrew University of Jerusalem (to A.Z.), and the Young clinician’s grant, Hadassah – Hebrew University Medical Center (to Y.R.

Spermidine Promotes Human Hair Growth and Is a Novel Modulator of Human Epithelial Stem Cell Functions

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Reduction in Inter-Hemispheric Connectivity in Disorders of Consciousness

Clinical diagnosis of disorders of consciousness (DOC) caused by brain injury poses great challenges since patients are often behaviorally unresponsive. A promising new approach towards objective DOC diagnosis may be offered by the analysis of ultra-slow (<0.1 Hz) spontaneous brain activity fluctuations measured with functional magnetic resonance imaging (fMRI) during the resting-state. Previous work has shown reduced functional connectivity within the “default network”, a subset of regions known to be deactivated during engaging tasks, which correlated with the degree of consciousness impairment. However, it remains unclear whether the breakdown of connectivity is restricted to the “default network”, and to what degree changes in functional connectivity can be observed at the single subject level. Here, we analyzed resting-state inter-hemispheric connectivity in three homotopic regions of interest, which could reliably be identified based on distinct anatomical landmarks, and were part of the “Extrinsic” (externally oriented, task positive) network (pre- and postcentral gyrus, and intraparietal sulcus). Resting-state fMRI data were acquired for a group of 11 healthy subjects and 8 DOC patients. At the group level, our results indicate decreased inter-hemispheric functional connectivity in subjects with impaired awareness as compared to subjects with intact awareness. Individual connectivity scores significantly correlated with the degree of consciousness. Furthermore, a single-case statistic indicated a significant deviation from the healthy sample in 5/8 patients. Importantly, of the three patients whose connectivity indices were comparable to the healthy sample, one was diagnosed as locked-in. Taken together, our results further highlight the clinical potential of resting-state connectivity analysis and might guide the way towards a connectivity measure complementing existing DOC diagnosis

Neuroendocrine Controls of Keratin Expression in Human Skin

The human skin serves as a source for a large number of neurohormones and neuropeptides, which affect skin biology on multiple different levels. Intriguingly, this includes the control of keratin expression by neurohormones such as thyrotropin-releasing hormone, thyrotropin, opioids, prolactin, and cannabinoid receptor 1-ligands. While this neuroendocrine regulation of human keratin biology in situ is likely to be involved in the maintenance of skin and hair follicle homeostasis and may participate in skin pathology, this regulation remains to be appreciated and explored by mainstream keratin research. Here, we review recent progress in this frontier of neuroendocrine and keratin skin research, define the many open questions in the field, and elaborate how neurohormones may be harnessed to treat selected genodermatoses and other skin disorders accompanied by abnormal keratin expression