Krutmann research group: environmentally-induced skin and lung aging

Head of research group:
Univ.-Prof. Dr. med. Jean Krutmann tl_files/bilder/mail.gif
Telephone: +49 (0)211-3389-225

Postdocs:
Dr. rer. nat. Marc Majora tl_files/bilder/mail.gif
Dr. med. Dr. rer. nat. Motoki Nakamura (together with Haarmann-Stemmann lab) tl_files/bilder/mail.gif
Dr. rer. nat. Kevin Sondenheimer tl_files/bilder/mail.gif
Dr. rer. nat. Julia Tigges (together with Fritsche lab) tl_files/bilder/mail.gif

PhD student:
Sabine Schneider tl_files/bilder/mail.gif

Technical assistance:
Maren Knechten, BTA tl_files/bilder/mail.gif
Ingo Uthe, BTA tl_files/bilder/mail.gif

Team Dr. Unfried:
Priv.-Doz. Dr. rer. nat. Klaus Unfried (senior researcher, head) tl_files/bilder/mail.gif
Dr. rer. nat. Tamara Hornstein tl_files/bilder/mail.gif
Tim Spannbrucker, PhD student tl_files/bilder/mail.gif

Team Prof. Dr. Boukamp:
Prof. Dr. rer. nat. Petra Boukamp (senior scientist, head) tl_files/bilder/mail.gif
Dr. rer. nat. Elizabeth Pavez Loriè, postdoc tl_files/bilder/mail.gif
Katharina Janke, PhD student tl_files/bilder/mail.gif
Philipp Worst, PhD student tl_files/bilder/mail.gif
More information

Research profile

The Krutmann research group investigates the molecular mechanisms that underlie environmentally-induced skin aging and associated skin diseases. Insights obtained hereby are translated into the development of novel preventive strategies, if possible. Main topics of the last years are: (1) the discovery of the promoting effects of solar IRA radiation on skin aging and the development of corresponding skin protection products, (2) studies on the functional relevance of UV-induced mitochondrial mutagenesis in skin aging, (3) system biology investigations regarding UV-induced stroma aging of the skin, (4) and the discovery of the first curative therapeutic approach for the UV-sensitive progeroid syndrome Cockayne syndrome. Together with PD Dr. K. Unfried the development of an Ectoin-based medical product for the prevention of airborne particle (PM) induced lung aging was recently achieved. In IUF internal cooperation on epidemiological studies, an association between PM-exposure and skin aging was described for the first time. This finding is currently further investigated in a large Chinese cohort and moreover mechanistically investigated. In cooperation with the toxicological working groups, the role of the aryl hydrocarbon receptor in PM- and UV-induced skin aging and carcinogenesis is respectively analyzed. In cooperation with the immunological working groups the role of the innate immune system in extrinsic skin aging is being investigated.

Projects

The project „Retrograde signaling responses in extrinsic skin aging“ (funded by the DFG Kr 871/5-1) deals with the elucidation of the mechanisms that are involved in skin aging induced by solar radiation. According to current understanding, this type of extrinsic skin aging is a result of the interaction of two fundamentally different biological processes: (i) acutely arising, transient active stress responses and (ii) permanently developing damage mechanisms that are based on the accumulation of damaged macromolecules. Both cases result in a similar / identical biological pathways that lead e.g. to an enhanced activation of matrix metalloproteases (MMP) and thereby to an enhanced degradation of collagen fibers. The essentials of the signal events involved in the formation of acute stress responses have been elucidated. Today we know that they cannot only be triggered by ultraviolet (UV) B and UV A radiation but also by infrared A (IR-A) radiation. In recent years we could show within the SFB 728 that the IRA-response results primarily from a transient influence on mitochondrial functions in dermal fibroblasts and is then transduced from mitochondria to the nucleus. Here, this response results in a change of the transcriptome leading to an altered expression of certain genes and finally activity alteration of their corresponding protein products, e.g. MMP-1, which is functionally important for the skin aging process.  The IRA-mediated cellular response is categorized as a retrograde signaling response. Interestingly, retrograde signaling responses are also involved in skin aging which is based on the accumulation of damaged macromolecules. In line with this, we demonstrated earlier that chronic UV irradiation induces the accumulation of mitochondrial (mt) DNA deletions in dermal fibroblasts of human skin and that the presence of these mtDNA deletions permanently changes the functions of the affected mitochondria. This results in a retrograde signaling process leading to an enhanced expression and activity of MMP-1 and to collagen degradation. In this project we now test the hypothesis that transient and permanent disturbances of the mt integrity trigger different retrograde signaling processes whose combination leads to an enhanced and accelerated extrinsic aging process in the skin.

The project "Gerontosys: Systems Biology of Stromal Aging" was initially funded by the Federal Ministry of Education and Research. Current activities are mainly covered by industry means. A systems biology analysis of intrinsic and extrinsic aging processes in the model of human skin fibroblasts is being conducted in a network of researchers from Düsseldorf and Heidelberg. The IUF is hereby in charge of the generation of a biobank of human skin fibroblasts that are obtained from extrinsic and intrinsic aged skin of volunteers of different age groups. Moreover, the IUF performs comparative investigations on mitochondrial and epigenetic function parameters.

The project „The role of the Cockayne syndrome B (CSB) protein in extrinsic aging processes“ (initially funded within the SFB 728, currently by iBRAIN und additional means from the industry) investigates the mechanisms that are involved in premature aging processes triggered through exogenic noxious agents in the progeroid syndrome Cockayne syndrome which is mainly caused by mutations in the CSB gene. We were able to show that the aggravation of the skin aging phenotype of CSB-deficient mice and human fibroblasts upon UV radiation can be ascribed to disturbances in autophagic processes. Together with the Ventura research group, very similar findings in C. elegans were made. Based on this, for the first time we identified a therapeutic approach which was able to rescue the skin phenotype of the mouse model. Current research aims to elucidate the molecular mechanisms that are responsible for this curative effect. Besides an accelerated skin aging phenotype, patients show neurodegenerative changes. As these are only mildly pronounced in the mouse model, differentiated human neurospheres are currently generated from human iPS cells derived from CS patients and phenotypically and functionally characterized. This work is conducted in close colaboration with the Fritsche research group.

The project „KAUVIR: Combination instead of addition: UV and IR radiation in the development of cancer and aging “ (funded by the Federal Ministry of Education and Research; conducted together with the team Dr. Boukamp) deals with the interaction between different wavelength ranges that are part of the natural sunlight and lead to biological reactions in human skin. The radiation spectrum of the sun contains UVA, UVB, visible light (VIS) und infrared (IR) radiation that each has specific profiles concerning their effects and cellular damage potential. We were able to show that combinations of radiation e.g. UV and IR do not compulsorily lead to an addition of the changes caused by the single spectrum but to an unexpected third or even neutralizing reaction. Therefore, this project investigates the combined action of UV and IR radiation regarding their biological effects on the skin at different levels. Using 2 dimensional and 3 dimensional organotypic cultures, the mouse model as well as in vivo in human skin the corresponding effects of the combined radiation compared to the single radiation is analyzed on cellular, genetic and epigenetic levels. Moreover, together with the research groups Haarmann-Stemmann, Esser and Fritsche investigations concerning the role of the AhR in photocarcinogenesis, extrinsic (UV and PM-triggered) skin aging, pathogenesis of inflammation reactions in the skin are being conducted. This work is supported by a scholarship of the Nagoya City University, Japan, as well as industry means.

The project "Identification of cellular responses relevant for the safety assessment of modern nanomaterials" (Head: Dr. Unfried) deals with the development of test systems for the identification and assessment of risks of these materials for humans. In the framework of the Leibniz PhD project based on complementary expertise at the IUF and the “INM - Leibniz-Institut für Neue Materialien” in Saarbrücken, mechanistic basics to establish those test systems shall be developed. This project is created as an integral part of the Alliance Nanosafety of the Leibniz Association with research work at both institutes.

The project "Identification of molecular mechanisms of carbon nanoparticle-induced senescence and aging ex vivo and in vivo: Role of reactive oxygen species" is a partial project of a jointly DFG individual application that was obtained together with the Haendeler research group. Both groups could show the induction of cellular senescence in lung epithelial cells as well as endothelial cells in jointly preparatory work (Büchner et al., 2013). The partial project, which is led by Dr. Unfried, investigates the molecular mechanisms of the formation of reactive oxygen species in primary human lung epithelial cells upon contact with environmental relevant carbon particles. The relevance of these events for the cellular senescence and the development of aging phenotypes in the lung is validated in cell cultures as well as suitable animal models.

Service

The Krutmann research group is together with Dr. S. Grether-Beck in charge of the IUF’s „Human in vivo studies“ (Heads: Prof. Dr. J. Krutmann, Dr. S. Grether-Beck).

Cooperations

IUF internal:
Esser research group
Fritsche research group
Haendeler research group
Schikowski junior research group
Schins research group
von Mikecz research group
Haarmann-Stemmann junior research group
Ventura liaison research group
Weighardt liaison research group

National:
Prof. Mark Berneburg, University Hospital Regensburg
Dr. Annette Kraegeloh, Leibniz Institute for New Materials (INM), Saarbrücken und Leibniz Alliance Nanosafety
Dr. Harald Jungnickel, Federal Institute for risk assessment (BfR), Berlin
Dr. Ingrid Haußer-Siller, University Hospital Heidelberg

International:
Prof. Jean-Marc Egly, University of Strasbourg, France
Dr. Ivana Fenoglio, PhD, Dipartimento di Chimica, Università degli Studi di Torino, Italy
Dr. Fernando Larcher, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain
Dr. Sijia Wang, PICB, Shanghai, China

Selected publications

Kroker M, Sydlik U, Autengruber A, Cavelius C, Weighardt H, Kraegeloh A, Unfried K: Preventing carbon nanoparticle-induced lung inflammation reduces antigen-specific sensitization and subsequent allergic reactions in a mouse model. Part Fibre Toxicol 12(1): 20, 2015. [pubmed] (open access)

Sydlik U, Peuschel H, Paunel-Görgülü A, Keymel S, Krämer U, Weissenberg A, Kroker M, Seghrouchni S, Heiss C, Windolf J, Bilstein A, Kelm M, Krutmann J, Unfried K: Recovery of neutrophil apoptosis by ectoine: a new strategy against lung inflammation. Eur Respir J 41(2): 433-442, 2013. [pubmed]

Kamenisch Y*, Fousteri M*, Knoch J, von Thaler AK, Fehrenbacher B, Dolle M, Kuiper R, Majora M, Schaller M, van Steeg H, Röcken M, Krutmann J*, Mullenders LH*, Berneburg M: Proteins of nucleotide and base excision repair pathways interact in mitochondria to protect from loss of subcutaneous fat, a hallmark of aging. J Exp Med 207(2): 379-390, 2010. (* equal contribution) [pubmed] (open access)

Fritsche E, Schäfer C, Bernsmann T, Calles C, Wurm M, Hübenthal U, Cline J E, Schroeder P, Rannug A, Klotz L O, Fürst P, Hanenberg H, Abel J, Krutmann J: Lightening up the UV response by identification of the Arylhydrocarbon Receptor as a cytoplasmatic target for ultraviolet B radiation. Proc Natl Acad Sci USA 104(21): 8851-8856, 2007. [pubmed] (open access)

Schwarz A, Ständer S, Berneburg M, Böhm M, Kulms D, van Steeg H, Große-Heitmeyer K, Krutmann J, Schwarz T: Interleukin-12 suppresses ultraviolet radiation-induced apoptosis by inducing DNA repair. Nature Cell Biol 4(1): 26-31, 2002. [pubmed]

Grether-Beck S, Bonnizi G, Felsner I, Timmer A, Schmitt-Brenden H, Sies H, Johnson JP, Piette J, Krutmann J: Non-enzymatic triggering of the ceramide signaling cascade by solar ultraviolet A radiation. EMBO J 19(21): 5793-5800, 2000. [pubmed] (open access)

Stege H, Roza L, Vink AA, Grewe M, Ruzicka T, Grether-Beck S, Krutmann J: Enzyme plus light therapy to repair DNA damage in ultraviolet-B-irradiated human skin. Proc Natl Acad Sci USA 97: 1790-1795, 2000. [pubmed] (open access)