A transactivation switchboard in wound healing

LBK

Current translational potential and underlying molecular mechanisms of necroptosis

Cell death has a fundamental impact on the evolution of degenerative disorders, autoimmune processes, inflammatory diseases, tumor formation and immune surveillance. Over the past couple of decades extensive studies have uncovered novel cell death pathways, which are independent of apoptosis. Among these is necroptosis, a tightly regulated, inflammatory form of cell death. Necroptosis contribute to the pathogenesis of many diseases and in this review, we will focus exclusively on necroptosis in humans. Necroptosis is considered a backup mechanism of apoptosis, but the in vivo appearance of necroptosis indicates that both caspase-mediated and caspase-independent mechanisms control necroptosis. Necroptosis is regulated on multiple levels, from the transcription, to the stability and posttranslational modifications of the necrosome components, to the availability of molecular interaction partners and the localization of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL). Accordingly, we classified the role of more than seventy molecules in necroptotic signaling based on consistent in vitro or in vivo evidence to understand the molecular background of necroptosis and to find opportunities where regulating the intensity and the modality of cell death could be exploited in clinical interventions. Necroptosis specific inhibitors are under development, but >20 drugs, already used in the treatment of various diseases, have the potential to regulate necroptosis. By listing necroptosis-modulated human diseases and cataloging the currently available drug-repertoire to modify necroptosis intensity, we hope to kick-start approaches with immediate translational potential. We also indicate where necroptosis regulating capacity should be considered in the current applications of these drugs

Pruritus: A Sensory Symptom Generated in Cutaneous Immuno-Neuronal Crosstalk

Pruritus or itch generated in the skin is one of the most widespread symptoms associated with various dermatological and systemic (immunological) conditions. Although many details about the molecular mechanisms of the development of both acute and chronic itch were uncovered in the last 2 decades, our understanding is still incomplete and the clinical management of pruritic conditions is one of the biggest challenges in daily dermatological practice. Recent research revealed molecular interactions between pruriceptive sensory neurons and surrounding cutaneous cell types including keratinocytes, as well as resident and transient cells of innate and adaptive immunity. Especially in inflammatory conditions, these cutaneous cells can produce various mediators, which can contribute to the excitation of pruriceptive sensory fibers resulting in itch sensation. There also exists significant communication in the opposite direction: sensory neurons can release mediators that maintain an inflamed, pruritic tissue-environment. In this review, we summarize the current knowledge about the sensory transduction of pruritus detailing the local intercellular interactions that generate itch. We especially emphasize the role of various pruritic mediators in the bidirectional crosstalk between cutaneous non-neuronal cells and sensory fibers. We also list various dermatoses and immunological conditions associated with itch, and discuss the potential immune-neuronal interactions promoting the development of pruritus in the particular diseases. These data may unveil putative new targets for antipruritic pharmacological interventions

The dual role of cannabidiol on monocyte-derived dendritic cell differentiation and maturation

IntroductionExtracts and compounds isolated from hemp (Cannabis sativa) are increasingly gaining popularity in the treatment of a number of diseases, with topical formulations for dermatological conditions leading the way. Phytocannabinoids such as ( )-cannabidiol, ( )-cannabinol and ( )-Δ9-tetrahydrocannabivarin (CBD, CBN, and THCV, respectively), are present in variable amounts in the plant, and have been shown to have mostly anti-inflammatory effects both in vitro and in vivo, albeit dominantly in murine models. The role of phytocannabinoids in regulating responses of dendritic cells (DCs) remains unclear.MethodsOur research aimed to investigate the effects of CBD, CBN, and THCV on human DCs differentiated from monocytes (moDCs). moDCs were treated with up to 10 μM of each phytocannabinoid, and their effects on viability, differentiation, and maturation were assessed both alone, and in conjunction with TLR agonists. The effects of CBD on cytokine production, T cell activation and polarization as well as the transcriptome of moDCs was also determined.ResultsPhytocannabinoids did not influence the viability of moDCs up to 10 μM, and only CBD had effects on maturational markers of moDCs, and neither compound influenced LPS-induced activation at 10 μM. Since only CBD had measurable effects on moDCs, in our subsequent experiments we tested the effect only of that pCB. On moDCs differentiated in the presence of CBD subsequent activation by LPS induced a markedly different, much more tolerogenic response. CBD-treated moDCs also produced significantly more interleukin (IL)-6, TNFα and, importantly, IL-10 in response to LPS, which shows a shift toward anti-inflammatory signaling, as well as a more robust secretory response in general. To rule out the possibility that these effects of CBD are specific to TLR4 signaling, we determined the effect of CBD on TLR7/8-induced maturation as well, and saw similar, although less marked responses. CBD-treated moDCs were also less efficient at activating naïve T cells after LPS stimulation, further supporting the tolerogenic effect of this phytocannabinoid on moDCs. Reactome pathway analysis showed an inflammatory response to LPS in moDCs, and to a lesser extent to CBD as well. In contrast CBD-treated moDCs responded to LPS with a shift towards a more tolerogenic phenotype, as IL-10 signaling was the most prominently induced pathway in this group.DiscussionOur results show that CBD achieves an anti-inflammatory effect on adaptive immune responses only in the presence of an activating stimuli on moDCs by reprogramming cells during long-term treatment, and not through acute, short-term effects

Az endocannabinoid rendszer szerepe és szabályozása a humán faggyúmirigyben = Role and regulation of the endocannabinoid system in the human sebaceous gland

Nagymértékben fókuszált, alapkutatási projektünkben – melyet egy szakértő, multidiszciplináris kutatói team nemzetközi kollaboráció keretében valósított meg – szisztematikusan és mechanisztikusan térképeztük fel az endokannabinoid rendszer (ECS) szerepét a humán faggyúmirigy biológiai folyamatainak szabályozásában. Humán tenyésztett sebocytákat, valamint humán bőrmintákat felhasználva kimutattuk, hogy az ECS elemei funkcionális formában fejeződnek ki a faggyúmirigyben. Emellett egy növényi nem pszichoaktív fitokannabinoidról, a Cannabidiolról bebizonyítottuk, hogy nagy hatékonyságú univerzális szebosztatikus ágensként működik, hiszen meggátolta számos mediátor faggyútermelést fokozó hatását. Megállapítottuk továbbá, hogy az ECS részt vehet bizonyos hormonok (pl. tesztoszteron) lipogén hatásainak kifejlődésében. Végezetül kimutattuk azt is, hogy az ECS egyes elemeinek kifejeződése jelentősen módosult acne vulgarisban szenvedők bőrmintáiban. Mindezen adatok arra utalnak, hogy az ECS meghatározó szereppel bír a humán faggyúmirigy folyamatainak szabályozásában fiziológiás és kóros körülmények között egyaránt. | In our highly focused, basic research project performed by an expert, multidisciplinary, international research team, we have systematically and mechanistically investigated the role and regulation of the endocannabinoid system (ECS) in the biology of the human sebaceous gland. Using cultured human sebocytes as well as human skin samples, we have found that the elements of the ECS are functionally expressed in the human sebaceous gland. Moreover, we have identified Cannabidiol, a non-psychoactive phytocannabinoid, as a highly efficient, universal sebostatic agent which inhibits the lipid synthesis-promoting actions of various mediators. In addition, we have shown that the ECS may act as a mediator of the lipogenic actions of certain hormones such as e.g. testosterone. Finally, we have found that the expression of members of the ECS is markedly altered in samples obtained from patients with acne vulgaris. These data suggest that the ECS plays a key role in the regulation of human sebaceous functions under physiological and pathological conditions

Opioidergic Signaling — A Neglected, Yet Potentially Important Player in Atopic Dermatitis

Atopic dermatitis (AD) is one of the most common skin diseases, the prevalence of which is especially high among children. Although our understanding about its pathogenesis has substantially grown in recent years, and hence, several novel therapeutic targets have been successfully exploited in the management of the disease, we still lack curative treatments for it. Thus, there is an unmet societal demand to identify further details of its pathogenesis to thereby pave the way for novel therapeutic approaches with favorable side effect profiles. It is commonly accepted that dysfunction of the complex cutaneous barrier plays a central role in the development of AD; therefore, the signaling pathways involved in the regulation of this quite complex process are likely to be involved in the pathogenesis of the disease and can provide novel, promising, yet unexplored therapeutic targets. Thus, in the current review, we aim to summarize the available potentially AD-relevant data regarding one such signaling pathway, namely cutaneous opioidergic signaling