Holger Schrumpf

Epidermal EGFR Controls Cutaneous Host Defense and Prevents Inflammation

Epidermal EGFR regulates skin inflammation and contributes to skin barrier function and host defense. Skin-Deep Search for the Effects of EGFR Inhibitors The goal of all medical interventions is to treat disease while minimizing the damage to healthy tissues in the body. This can be difficult to achieve for cancer drugs, however, especially when the effectiveness of a drug directly correlates with its side effects, as is the case for inhibitors of the epidermal growth factor receptor (EGFR). EGFR inhibitors are particularly known for causing a severe rash and skin damage, which sometimes forces patients to prematurely stop their treatments. Now, two papers by Mascia et al. and Lichtenberger et al. help clarify the mechanism of rash formation induced by EGFR inhibitors and uncover some of the skin components that contribute to this phenomenon. Both sets of authors used mouse models that lack EGFR only in the skin to replicate the pattern of injury seen in patients treated with EGFR inhibitors. They characterized the changes in chemokine expression in the skin of treated patients and study animals and examined the effects of EGFR inhibition on skin defenses and bacteria. They also investigated the effects of crossing mice that lack EGFR in the skin with mice deficient in different immune pathways and immune cell types to determine which ones are necessary for the rash phenotype. The findings of these two studies suggest that EGFR signaling is important for normal skin barrier function and antimicrobial defense, and that skin macrophages may contribute to the adverse effects of EGFR inhibitors. Additional work will be necessary to further expand our understanding of EGFR inhibitor toxicity and to continue the search for ways to prevent this disruptive side effect. The current studies provide mechanistic insights that should help guide further investigation in this area. The epidermal growth factor receptor (EGFR) plays an important role in tissue homeostasis and tumor progression. However, cancer patients treated with EGFR inhibitors (EGFRIs) frequently develop acneiform skin toxicities, which are a strong predictor of a patient’s treatment response. We show that the early inflammatory infiltrate of the skin rash induced by EGFRI is dominated by dendritic cells, macrophages, granulocytes, mast cells, and T cells. EGFRIs induce the expression of chemokines (CCL2, CCL5, CCL27, and CXCL14) in epidermal keratinocytes and impair the production of antimicrobial peptides and skin barrier proteins. Correspondingly, EGFRI-treated keratinocytes facilitate lymphocyte recruitment but show a considerably reduced cytotoxic activity against Staphylococcus aureus. Mice lacking epidermal EGFR (EGFRΔep) show a similar phenotype, which is accompanied by chemokine-driven skin inflammation, hair follicle degeneration, decreased host defense, and deficient skin barrier function, as well as early lethality. Skin toxicities were not ameliorated in a Rag2-, MyD88-, and CCL2-deficient background or in mice lacking epidermal Langerhans cells. The skin phenotype was also not rescued in a hairless (hr/hr) background, demonstrating that skin inflammation is not induced by hair follicle degeneration. Treatment with mast cell inhibitors reduced the immigration of T cells, suggesting that mast cells play a role in the EGFRI-mediated skin pathology. Our findings demonstrate that EGFR signaling in keratinocytes regulates key factors involved in skin inflammation, barrier function, and innate host defense, providing insights into the mechanisms underlying EGFRI-induced skin pathologies.

The top skin-associated genes: a comparative analysis of human and mouse skin transcriptomes

Abstract The mouse represents a key model system for the study of the physiology and biochemistry of skin. Comparison of skin between mouse and human is critical for interpretation and application of data from mouse experiments to human disease. Here, we review the current knowledge on structure and immunology of mouse and human skin. Moreover, we present a systematic comparison of human and mouse skin transcriptomes. To this end, we have recently used a genome-wide database of human gene expression to identify genes highly expressed in skin, with no, or limited expression elsewhere – human skin-associated genes (hSAGs). Analysis of our set of hSAGs allowed us to generate a comprehensive molecular characterization of healthy human skin. Here, we used a similar database to generate a list of mouse skin-associated genes (mSAGs). A comparative analysis between the top human (n=666) and mouse (n=873) skin-associated genes (SAGs) revealed a total of only 30.2% identity between the two lists. The majority of shared genes encode proteins that participate in structural and barrier functions. Analysis of the top functional annotation terms revealed an overlap for morphogenesis, cell adhesion, structure, and signal transduction. The results of this analysis, discussed in the context of published data, illustrate the diversity between the molecular make up of skin of both species and grants a probable explanation, why results generated in murine in vivo models often fail to translate into the human.

METEORIN-LIKE is a cytokine associated with barrier tissues and alternatively activated macrophages.

Cytokines are involved in many functions of the immune system including initiating, amplifying and resolving immune responses. Through bioinformatics analyses of a comprehensive database of gene expression (BIGE: Body Index of Gene Expression) we observed that a small secreted protein encoded by a poorly characterized gene called meteorin-like (METRNL), is highly expressed in mucosal tissues, skin and activated macrophages. Further studies indicate that Metrnl is produced by Alternatively Activated Macrophages (AAM) and M-CSF cultured bone marrow macrophages (M2-like macrophages). In the skin, METRNL is expressed by resting fibroblasts and IFNγ-treated keratinocytes. A screen of human skin-associated diseases showed significant over-expression of METRNL in psoriasis, prurigo nodularis, actinic keratosis and atopic dermatitis. METRNL is also up-regulated in synovial membranes of human rheumatoid arthritis. Taken together, these results indicate that Metrnl represents a novel cytokine, which is likely involved in both innate and acquired immune responses.

Systematic identification and characterization of novel human skin-associated genes encoding membrane and secreted proteins.

Through bioinformatics analyses of a human gene expression database representing 105 different tissues and cell types, we identified 687 skin-associated genes that are selectively and highly expressed in human skin. Over 50 of these represent uncharacterized genes not previously associated with skin and include a subset that encode novel secreted and plasma membrane proteins. The high levels of skin-associated expression for eight of these novel therapeutic target genes were confirmed by semi-quantitative real time PCR, western blot and immunohistochemical analyses of normal skin and skin-derived cell lines. Four of these are expressed specifically by epidermal keratinocytes; two that encode G-protein-coupled receptors (GPR87 and GPR115), and two that encode secreted proteins (WFDC5 and SERPINB7). Further analyses using cytokine-activated and terminally differentiated human primary keratinocytes or a panel of common inflammatory, autoimmune or malignant skin diseases revealed distinct patterns of regulation as well as disease associations that point to important roles in cutaneous homeostasis and disease. Some of these novel uncharacterized skin genes may represent potential biomarkers or drug targets for the development of future diagnostics or therapeutics.

Laser assisted Drug Delivery: Grundlagen und Praxis.

Die topische Applikation von Wirkstoffen ist eine zentrale Therapieoption der Dermatologie. Allerdings mindert die effektive Barrierefunktion der Haut die Bioverfügbarkeit der meisten Externa.

Mechanisms underpinning protection against eccentric exercise-induced muscle damage by ischemic preconditioning

Eccentric exercise training is effective for increasing muscle mass and strength, and improving insulin sensitivity and blood lipid profiles. However, potential muscle damage symptoms such as prolonged loss of muscle function and delayed onset of muscle soreness may restrict the use of eccentric exercise, especially in clinical populations. Therefore, strategies to reduce eccentric exercise-induced muscle damage (EIMD) are necessary, and an extensive number of scientific studies have tried to identify potential intervention modalities to perform eccentric exercises without adverse effects. The present paper is based on a narrative review of current literature, and provides a novel hypothesis by which an ischemic preconditioning (IPC) of the extremities may reduce EIMD. IPC consists of an intermittent application of short-time non-lethal ischemia to an extremity (e.g. using a tourniquet) followed by reperfusion and was discovered in clinical settings in an attempt to minimize inflammatory responses induced by ischemia and ischemia-reperfusion-injury (I/R-Injury) during surgery. The present hypothesis is based on morphological and biochemical similarities in the pathophysiology of skeletal muscle damage during clinical surgery and EIMD. Even though the primary origin of stress differs between I/R-Injury and EIMD, subsequent cellular alterations characterized by an intracellular accumulation of Ca2+, an increased production of reactive oxygen species or increased apoptotic signaling are essential elements for both. Moreover, the incipient immune response appears to be similar in I/R-Injury and EIMD, which is indicated by an infiltration of leukocytes into the damaged soft-tissue. Thus far, IPC is considered as a potential intervention strategy in the area of cardiovascular or orthopedic surgery and provides significant impact on soft-tissue protection and downregulation of undesired excessive inflammation induced by I/R-Injury. Based on the known major impact of IPC on skeletal muscle physiology and immunology, the present paper aims to illustrate the potential protective effects of IPC on EIMD by discussing possible underlying mechanisms.

Arzneimittelreaktionen bei antineoplastischen Substanzen

In recent years, several new classes of compounds have successfully been established in the treatment of cancer. They selectively inhibit disturbed signaling pathways or induce anti-tumor immune responses. These novel targeted cancer drugs show a favorable safety profile compared to conventional chemotherapeutic agents. The most important side effects of these anticancer agents include cutaneous reactions and occur in a time-dependant manner and show class-specific patterns. In this review article, we compare the cutaneous side effects of epidermal growth factor inhibitors (EGFRI), multikinase inhibitors (MKI), BRAF inhibitors (BRAFI), mTor inhibitors (mTorI) and immune checkpoint inhibitors and discuss severity-adapted management strategies.ZusammenfassungIn den letzten Jahren konnten zahlreiche neue Substanzklassen erfolgreich zur Therapie von Tumoren etabliert werden. Diese greifen hochselektiv in gestörte Regulationsvorgänge oder immunologische Regression maligner Zellen ein und weisen daher im Vergleich zu konventionellen Chemotherapeutika ein günstiges Verträglichkeitsprofil auf. Als bedeutendste Nebenwirkungen dieser antineoplastischen Substanzen gelten zum einen vielfältige kutane Reaktionen, die behandlungszeitabhängig in substanzklassenspezifischen Mustern auftreten, und zum anderen autoimmune Phänomene. In dieser Übersichtsarbeit vergleichen wir die kutanen Nebenwirkungen der epidermalen Wachstumsfaktorinhibitoren (EGFRI), Multikinaseinhibitoren (MKI), BRAF-Inhibitoren (BRAFI), mTOR-Inhibitoren (mToRI) sowie Immuncheckpoint-Inhibitoren und diskutieren befundadaptierte Therapieoptionen.AbstractIn recent years, several new classes of compounds have successfully been established in the treatment of cancer. They selectively inhibit disturbed signaling pathways or induce anti-tumor immune responses. These novel targeted cancer drugs show a favorable safety profile compared to conventional chemotherapeutic agents. The most important side effects of these anticancer agents include cutaneous reactions and occur in a time-dependant manner and show class-specific patterns. In this review article, we compare the cutaneous side effects of epidermal growth factor inhibitors (EGFRI), multikinase inhibitors (MKI), BRAF inhibitors (BRAFI), mTor inhibitors (mTorI) and immune checkpoint inhibitors and discuss severity-adapted management strategies.

Retrospective analysis of the frequency of centrofacial telangiectasia in systemic sclerosis patients treated with bosentan or ilomedin.

BackgroundBosentan is a dual endothelin receptor antagonist initially introduced for the treatment of pulmonary arterial hypertension and recently approved for the treatment of digital ulcers in patients with systemic sclerosis (SSc). Our clinical observations indicate that bosentan therapy may be associated with an increased frequency of centrofacial telangiectasia (TAE). Here, we sought to analyze the frequency of TAE in patients with SSc who were treated with either bosentan or the prostacyclin analog iloprost.MethodsWe conducted a retrospective analysis in 27 patients with SSc undergoing therapy with either bosentan (n = 11) or iloprost (n = 16). Standardized photodocumentations of all patients (n = 27) were obtained at a time point ten months after therapy initiation and analyzed. A subgroup of patients (bosentan: n = 6; iloprost: n = 6) was additionally photodocumented prior to therapy initiation, enabling an intraindividual analysis over the course of therapy.ResultsAfter ten months of therapy patients with SSc receiving bosentan showed a significantly (P = 0.0028) higher frequency of centrofacial TAE (41.6 ± 27.8) as compared to patients with SSc receiving iloprost (14.3 ± 13.1). Detailed subgroup analysis revealed that the frequency of TAE in the bosentan group (n = 6 patients) increased markedly and significantly (P = 0.027) by 44.4 after ten months of therapy (TAE at therapy initiation: 10.8 ± 5.1; TAE after ten months of therapy: 55.2 ± 29.8), whereas an only minor increase of 1.9 was observed in the iloprost group (n = 6 patients; TAE at therapy initiation: 18.3 ± 14.5; TAE after ten months of therapy: 20.2 ± 15.5), yet without reaching statistical significance (P = 0.420).ConclusionsThe use of bosentan may be associated with an increased frequency of TAE in patients with SSc. Patients should be informed about this potential adverse effect prior to therapy. Treatment options may include camouflage or laser therapy.

Preventively enteral application of immunoglobulin enriched colostrums milk can modulate postoperative inflammatory response

Several studies demonstrated acute inflammatory response following traumatic injury. Inflammatory response during surgical interventions was verified by a significant increase of endotoxin plasma levels and a decrease of the endotoxin neutralizing capacity (ENC). However, the incidence of elevated endotoxin levels was significantly higher (89%) than detected bacterial translocation (35%). Thus parts or products of Gram-negative bacteria seem to translocate more easily into the blood circulation than whole bacteria. Along with the bacterial translocation, the inflammatory response correlated directly with the severity of the surgical intervention. In comparison after major and minor surgery Interleukin-6 (IL-6) and C-reactive protein (CRP) was also significantly different. Similar effects in mediator release were shown during endovascular stent graft placement and open surgery in infrarenal aortic aneurysm. Open surgery demonstrated a significant stronger endotoxin translocation and a decrease of ENC. Strategies to prevent translocation seem to be sensible. Colostrum is the first milk produced by the mammary glands within the first days after birth. It contains a complex system of immune factors and has a long history of use in traditional medicine. Placebo-controlled studies verified that prophylactic oral application of immunoglobulin-enriched colostrum milk preparation diminishes perioperative endotoxemia, prevents reduction of ENC and reduces postoperative CRP-levels, suggesting a stabilization of the gut barrier. This effect may be caused by immunoglobulin transportation by the neonatal receptor FcRn of the mucosal epithelium.In conclusion, there is an association of perioperative endotoxemia and the subsequent increase in mediators of the acute phase reaction in surgical patients. A prophylactic oral application of colostrum milk is likely to stabilize the gut barrier i.e. reduces the influx of lipopolysaccharides arising from Gram-negative bacterial pathogens and inhibits enterogenic endotoxemia. This appears to be a major mechanism underlying the therapeutic effect in patients at risk for Gram-negative septic shock.

Laser-assisted drug delivery: mode of action and use in daily clinical practice.

Topical application of pharmaceutical agents is a basic principle of dermatological therapy. However, the effective barrier function of the skin significantly impairs the bioavailability of most topical drugs. Fractional ablative lasers represent an innovative strategy to overcome the epidermal barrier in a standardized, contact‐free manner. The bioavailability of topical agents can be significantly enhanced using laser‐assisted drug delivery (LADD). In recent years, the principle of LADD has become well established for various dermatological indications. Herein, we review the current literature on LADD and present potential future applications.