Kliniken & Institute … SFBs SFB TRR156 Research 2. Funding Period Research Area C: “Skin…

Research Area C: “Skin and systemic immunity”

Area C focusses on the effect of skin immune reactions for triggering autoinflammatory diseases such as psoriasis, autoimmune blistering disease, or scleroderma.

C01 - Targets and mediators of IL-17 in mouse models of psoriasis and skin infection

Graphical abstract of the planned projects. Numbers in red circles indicate the respective project aims. 1. Which specific signals lead to expansion of T17 cells during S. aureus infections? 2. How does IL-17 affect KCs gene expression in psoriasis and infections? 3. What are the roles of the MALT1-NFB pathway and the NIK non-canonical NFB pathway in the KCs response to excessive IL-17A presence?

The IL-17 response plays a major role in the defense against S. aureus but also in the pathogenesis of psoriasis. As we are interested in the specific mechanism of IL-17 induction and its downstream pathways we will (i) investigate how T cells expressing IL-17 are induced by S. aureus infections; (ii) analyze the keratinocyte gene expression response to IL-17 in different models of psoriasis as well as in S. aureus infection; (iii) investigate the role of the MALT1-NFκB pathway and the NIK non-canonical NFκB pathway in the keratinocyte response to IL-17A.

Principal investigators

Prof. Dr. Ari Waisman

IInstitute for Molecular Medicine
University Medical Center
Johannes Gutenberg University Mainz

Dr. Florian Kurschus

Department of Dermatology
University Hospital Heidelberg
Heidelberg University

C03 - Impact of noncanonical NF-κB signaling during hapten-induced skin inflammation

Noncanonical NF-κB activation (NF-κB2) activation adapted from (2). Graphical representation of the interruption of NF-κB2 signaling in NIKaly/aly and NF-κB2-/- (NF-κB.p100-/-/p52-/-) mice. Deficiency in NIK prevents the phosphorylation of IKKα complex which is responsible for the phosphorylation of p100 and further processing to active subunit p52. Additionally, p100 binds RelB, hindering it from binding to other homodimers and translocation into the nucleus.

Our studies revealed that noncanonical NF-κB signaling is essential for adaptive immunity as mice deficient in NF-κB2 signaling were unable to develop progressive chronic contact hypersensitivity reactions. Thus, we aim to uncover how noncanonical NF-kB signaling modulates acute and chronic T cell driven inflammatory processes by (i) identifying the essential cellular players employing cell-type specific conditional NF-κB2-/- and NIKaly/aly mice in vivo, (ii) investigating cell specific impairments in activation, differentiation and survival in vitro, (iii) analyzing differences in T cell activation and leukocyte homing patterns in vivo and (iv) uncovering the efficacy of specific NF-κB2 inhibition in vitro and in vivo.

Principal investigators

Prof. Dr. Bernd Pichler

Department of Preclinical Imaging and Radiopharmacy
Werner Siemens Imaging Center
Eberhard Karls University of Tübingen

Dr. Manfred Kneilling

Department of Dermatology
Eberhard Karls University of Tübingen

C04 - Role of regulatory T cells in B cell-mediated autoimmune skin diseases

Autoimmune bullous dermatoses (AIBD) are severe autoantibody-mediated skin diseases. The pathogenic relevance of autoreactive CD4+ T cells for the induction of autoantibody production is unclear. We have previously shown that Treg-deficient Scurfy mice spontaneously develop autoantibodies against different AIBD autoantigens. Now we aim to further investigate this aspect of AIBD development in the Scurfy model: Our project will address, (i) which different types of AIBD develop in Scurfy mice, (ii) dissect the pathophysiologic mechanisms of the pathogenic autoantibodies and (iii) focus on targeting antigen-specific CD4+ T cells as therapeutic strategy in AIBD.

Principal investigators

Prof. Dr. med. Alexander Enk

Ärztlicher Direktor (Hautklinik)

C05 - Scleroderma: role of macrophages and dendritic cells in tissue fibrosis

Scleroderma: role of macrophages and dendritic cells in tissue fibrosis. CMP: Common myeloid progenitor, NCM: Non classical monocyte, CM: Classical monocyte, moDC: Monocyte-derived DC, DC: Dendritic cell, Fib: Fibroblast, ISG: Interferon stimulated gene, Nr4a1 Nuclear receptor 4a1, Treg: T regulatory cell, Teff: T effector cell

The function of monocyte/macrophage differentiation and of dendritic cells in the pathogenesis of scleroderma (Scl), the skin manifestation of systemic sclerosis with extensive fibrosis, is not clear. We will alter the frequency, polarization and migration of myeloid/dendritic cells to test Scl development and the underlying immune mechanisms in chemically induced and spontaneous models of the disease. In addition, we will compare these data with that of monocytes/myeloid cells in the blood and the skin of patients suffering from systemic sclerosis to identify key (innate) cellular myeloid drivers and dominant molecular mechanisms of Scl.

Principal investigators

Dr. Verena K. Raker

Div. of Experimental and Translational
Immunodermatology, Dep. of Dermatology
Center for Thrombosis and Hemostasis
University Medical Center 
Johannes Gutenberg University Mainz

Prof. Dr. Kerstin Steinbrink

Department of Dermatology
University Hospital Münster
Westfälische Wilhelms-University Münster

C06 - Wnt-associated Dkk3 in inflammatory and fibrosing skin disease

The Dickkopf protein family regulates Wnt pathway signalling, which exerts relevant effects on skin development and homeostasis. Thoracic radiation (20 Gray) of C57BL/6 mice leads to enhanced Dkk3 expression by keratinocytes, and an acute dermatitis, eventually developing into a chronic inflammatory/fibrosing process. By contrast, mice with a targeted deletion of Dkk3 (DKK3-/-) do not develop hyperplasia and chronic fibrosing inflammation. We hypothesize that canonical Wnt activation in concert with Dkk3 expression induces a compensatory hyperreactive epidermal hyperplasia with chronic dermal fibroblast/inflammatory activation and lipid dysregulation.

Radiation dermatitis can initiate a chronic inflammatory/fibrosing process. We found that Dickkopf-3 (Dkk3), a Wnt-related protein linked to immune regulation, promotes chronic fibrosing inflammation in mouse models of radiation damage. Dkk3 knockouts do not develop epidermal hyperplasia, or chronic dermal fibroblast/inflammatory activation. The proposal seeks to (i) identify the relevant cellular source of Dkk3 in radiation damaged skin using reporter mice and targeted Dkk3 knockouts, (ii) characterize Dkk3 effects on local macrophages and T cells, (iii) dissect the impact of Dkk-related signalling pathways using human skin models, and (iv) connect radiation-induced epigenetic modifications to expression of Dkk3 and chronic inflammatory fibrosis.

Principal investigators

PD Dr. Roger Sandhoff

DKFZ
Dept. of Cellular and Molecular Pathology

Prof. Dr. Peter Nelson

Medical Clinic and Policlinic IV
Ludwig-Maximilians-University München

C07 - PAR2 signaling in cutaneous inflammation

The three specific aims will analyze the role of PAR2 as a central mediator of skin inflammation. Aim 1 will use cell-type specific knock-outs to define the roles of PAR2 expressed by myeloid cells, keratinocytes, and sensory neurons for the inflammatory response in the hapten challenge. Aim 2 will investigate the contributions of macrophage-produced and blood-derived FXa to specific PAR2 activation in skin inflammation. Aim 3 will delineate the roles of cutaneous proteases (Prostasin, Matriptase and Kallikrein (KLK5)) expressed by skin epidermal cells to PAR2 activation in skin inflammation.

Proteolytic signaling through the G protein-coupled protease activated receptor (PAR) 2 promotes contact hypersensitivity (CHS) reactions, but relevant cell types and participating proteases are poorly defined. We will employ cell type-specific deletion of PAR2 in keratinocytes, sensory neurons and macrophages as well as novel mouse models with altered PAR2 signaling by specific proteases to delineate the contributions of PAR2 to skin inflammation. These experiments will reveal how coagulation and other proteases contribute to initiation and amplification of CHS responses and other inflammatory skin disorders.

Principal investigators

Prof. Dr. Wolfram Ruf

Center for Thrombosis and Hemostasis
University Medical Center 
Johannes Gutenberg University Mainz

C08 - Resolving the mechanisms of the skin-vasculature-crosstalk in psoriasis-associated vascular dysfunction

Psoriasis is a common skin condition manifested by high levels of the pro-inflammatory cytokine IL-17A. Ectopic expression of IL-17A by keratinocytes leads to the development of early skin inflammation followed by vascular inflammation and dysfunction as in patients with severe psoriasis. To investigate the link between psoriasis and vascular inflammation, we will 1.) study whether inflammatory cells can migrate from the skin to the cardiovascular system. 2.) Study whether ablation of neutrophils that invade the skin in psoriasis leads to diminished vascular disease. We will generate mice with specific deletion of CD18 in neutrophils, in order to prevent their extravasation via the vessel wall, to study the role of these cells in psoriasis-like skin disease and the associated vascular inflammation. 3) We plan to compare cytokine profiles in aorta, skin and blood of psoriatic mice to control animals and with skin and blood samples of psoriasis patients. 4) We will analyze if vascular inflammation in psoriasis can be inhibited by blocking IL-1 signaling.

Principal investigators

Prof. Ari Waisman

Institute for Molecular Medicine
University Medical Center
Johannes Gutenberg University Mainz

Dr. Susanne Helena Karbach

Center for Cardiology, Cardiology I
Center of Thrombosis and Hemostasis (CTH) and Institute for Molecular Medicine
University Medical Center
Johannes Gutenberg University Mainz