Kliniken & Institute ... Kliniken Hautklinik (Zentrum) ... Hautklinik Forschung Labor Prof. Dr. Schäkel...

Arbeitsgruppe Prof. Dr. Schäkel

Prof. Dr. med. Knut Schäkel

Ltd. Oberarzt (Hautklinik)
Arbeitsgruppenleiter (AG Prof. Dr. med. K. Schäkel)


06221 56-8511
06221 56-8510

Research Focus

We aim for a better understanding of the human immune system. Our laboratory studies immune responses relevant for chronic inflammatory diseases - psoriasis, atopic dermatitis and lupus erythematosus - as well malignant melanoma.

Dendritic cells, monocytes and macrophages are of central importance for the regulation of immune responses. They can be found at high numbers in the skin as well as in many other organs and are subdivided into populations with specific functional properties.

We previously defined a distinct population of highly-proinflammatory cells selectively expressing the marker antigen slan(6-sulfo lactosamine) on the homing molecule P-selectin glycoprotein ligand 1 (PSGL-1). These cells share phenotypic and functional features of dendritic cells and therefore, the name slan-dendritic cells was coined. As current gene expression studies reveal the relationship of slan-dendritic cells to monocytic cells, the exact nature of these cells and their precursor remains to be defined.

Slan-dendritic cells produce the T cell programming cytokines IL-12, IL-23 and IL-1ß at high levels and induce a strong Th1/Th17 T cell response.  In line with these functional features we recently identified slan-dendritic cells as inflammatory dermal dendritic cells in psoriasis and lupus erythematosus. In addition, current studies indicate a functional role for slan-dendritic cells in human cancer lymph-node metastasis, multiple sclerosis, Crohn's disease and viremic HIV infection.

The expression of highly functional TLR4, TLR7 and TLR8 receptors accounts for their low activation threshold and their proinflammatory potential in autoimmune diseases.  Other functional features of slan-dendritic cells are their outstanding capacity to bind immune complexes via the low affinity FcgRIIIa receptor (CD16a). The capacity to stimulate proinflammatory immune responses is large

Projects

Functional specialization of proinflammatory dendritic cells in Psoriasis

German Research Foundation; SCHA 1693/1-1

Functional specialization of proinflammatory dendritic cells in Psoriasis

Psoriasis is a common chronic inflammatory skin disease in which dendritic cells (DC) are thought to orchestrate the pathogenic Th17/Th1-dominated immune response. Our studies demonstrate the functional specialization of slan (6-sulfo LacNAc+) DC as an important proinflammatory DC subtype in psoriasis. Previously, we identified slanDC and reported on their proinflammatory function. In the meanwhile slanDC have also been described in other chronic inflammatory diseases such as lupus erythematosus, Crohns disease and multiple sclerosis. Skin lesion from psoriasis patients contain increased numbers of activated slanDC expressing the key proinflammatory molecules TNF-a, IL-23 and iNOS. Complexes of autologous nucleic acids and the antimicrobial peptide LL37 (Cathelicidin) triggering Toll-like receptors (TLR) are regarded as important stimuli for cell activation in psoriasis. For slanDC we could demonstrate expression of TLR7/8 and a high sensitivity to stimulation with LL37-complexed autologous RNA as well as synthetic TLR7- as well as TLR8- ligands. Stimulated slanDC can produce higher levels of the proinflammatory cytokines IL-23, IL-12, IL-1b as well as TNF-a than other DC subsets or monocytes and induce strong Th17/Th1-dominated immune responses. Our goal is to answer questions regarding the role of DC in the immunopathogenesis of psoriasis. Questions: 1. What is the in vivo relevance of slanDC for inducing and maintaining psoriasis skin inflammation? 2. Which unknown molecular and functional mechanisms allow slanDC to regulate the inflammatory immune response in psoriasis? 3. What is the spatial and temporal microanatomic localization of slanDC during the development and maintenance of psoriasis plaques? For these studies we will employ mouse models with human skin and leukocyte transplants, will develop targeting strategies for the depletion of slanDC, analyze gene expression of slanDC from lesional skin and correlate these findings with the microanatomic distribution of slanDC in the skin. We are convinced that the proposed study program has the potential to significantly increase our understanding of the immunopathogenesis of psoriasis and to identify new targets for therapeutic intervention in psoriasis. As slanDC play a proinflammatory role in different Th17/Th1 dominated chronic inflammatory diseases, the results of the propose work is potentially of broad interest.

Immune complex mediated and IgG Fc receptor dependent recruitment of leukocytes into the skin

German Research Foundation: Collaborative Research Center/ SFB Transregio 156, Project C02

Immune complex mediated and IgG Fc receptor dependent recruitment of leukocytes into the skin

Knut Schäkel, MD; Department of Dermatology
Florina Olaru, PhD; Department of Dermatology

The formation and deposition of immune complexes (IC) in the skin and other tissues plays an essential role in the generation of protective antimicrobial immunity as well as harmful autoimmune responses. The interaction of ICs with corresponding Fc receptors (FcR), is a crucial step in IC-triggered inflammation and contributes to the development and severity of several autoimmune diseases. We will test i) relevant parameters of IC that induce migration of FcgRIII expressing cells, ii) the signaling via FcR that induces dynamic cytoskeletal reorganization involved in leukocyte locomotion. iii) Mouse models for IC-mediated skin inflammation and antibody-mediated blistering diseases will help to unravel the pathophysiologic relevance of our findings in autoimmunity.

Project 12: Tumor-directed cytotoxicity of proinflammatory human dendritic cells and natural killer cells in malignant melanoma (MM)

German Research Foundation: Research Training Group: GRK 2099

Project 12: Tumor-directed cytotoxicity of proinflammatory human dendritic cells and natural killer cells in malignant melanoma (MM)

Knut Schäkel, MD; Department of Dermatology

Adelheid Cerwenka, PhD; German Cancer Research Center

Dendritic cells (DC) and natural killer (NK) cells collectively mount a strong anti-tumor immune responses. However, we have a limited understanding of how these populations crosstalk with each other and how we can exploit the NK/DC interaction for the therapy of malignant melanoma. In addition, it is unclear which subtypes of DC are most relevant for

inducing anti-tumor effector functions in the presence and absence of NK cells. In the proposed project, we will analyze the functional consequences and mechanisms of the NK/slanDC crosstalk in vitro and in vivo. The results gained in this project could lead to novel therapeutic strategies for the treatment of MM based on the exploitation of the slanDC/NK crosstalk.

Group members

Doktoranden/-innen

Post Docs

Technische Assistenten/-innen

Selected publications

  1. Heratizadeh A, Werfel T, Wollenberg A, Abraham S, Plank-Habibi S, Schnopp C, Sticherling M, Apfelbacher C, Biedermann T, Breuer K, Fell I, Fölster-Holst R, Heine G, Grimm J, Hennighausen L, Kugler C, Reese I, Ring J, Schäkel K, Schmitt J, Seikowski K, von Stebut E, Wagner N, Waßmann-Otto A, Wienke-Graul U, Weisshaar E, Worm M, Gieler U, Kupfer J; Arbeitsgemeinschaft : Neurodermitisschulung für Erwachsene (ARNE) Study Group. Effects of structured patient education in adults with atopic dermatitis: Multicenter randomized controlled Trial.J Allergy Clin Immunol. 2017 Sep;140(3):845-853
  2. Oehrl S, Olaru F, Kunze A, Maas M, Pezer S, Schmitz M, Schäkel K. Controlling the pro-inflammatory function of 6-sulfo LacNAc (slan) dendritic cells with dimethylfumarate.J Dermatol Sci. 2017 Sep;87(3):278-284.
  3. Oehrl S, Prakash H, Ebling A, Trenkler N, Wölbing P, Kunze A, Döbel D, Schmitz M, Enk A, Schäkel K: The phosphodiesterase 4 inhibitor apremilast inhibits Th1 but promotes Th17 responses induced by 6-sulfo LacNAc (slan) dendritic cells J Dermatol Sci, 2017 Aug;87(2):110-115.
  4. Guenova E, Skabytska Y, Hoetzenecker W, Weindl G, Sauer K, Tham M, Kim KW, Park JH, Seo JH, Ignatova D, Cozzio A, Levesque MP, Volz T, Köberle M, Kaesler S, Thomas P, Mailhammer R, Ghoreschi K, Schäkel K, Amarov B, Eichner M, Schaller M, Clark RA, Röcken M, Biedermann T: IL-4 abrogates T(H)17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells. Proc Natl Acad Sci U S A. 2015 Feb 17;112(7):2163-8.
  5. Vermi W, Micheletti A, Lonardi S, Costantini C, Calzetti F, Nascimbeni R, Bugatti M, Codazzi M, Pinter PC, Schäkel K, Tamassia N, Cassatella MA: slanDCs selectively accumulate in carcinoma-draining lymph nodes and marginate metastatic cells. Nat Commun. 2014;5:3029.
  6. Döbel T, Kunze A, Babatz J, Tränkner K, Ludwig A, Schmitz M, Enk A, Schäkel K: FcγRIII (CD16) equips immature 6-sulfo LacNAc-expressing dendritic cells (slanDCs) with a unique capacity to handle IgG-complexed antigens. Blood. 2013 (18) 3609-18.
  7. Hänsel A, Günther C, Baran W, Bidier M, Lorenz HM, Schmitz M, Bachmann M, Döbel T, Enk AH, Schäkel K: Human 6-sulfo LacNAc (slan) dendritic cells have molecular and functional features of an important pro-inflammatory cell type in lupus erythematosus. J Autoimmun. 2013 (40) 1-8.
  8. Hänsel A, Günther C, Ingwersen J, Starke J, Schmitz M, Bachmann M, Meurer M, Rieber EP, Schäkel K: Human slan (6-sulfo LacNAc) dendritic cells are inflammatory dermal dendritic cells in psoriasis and drive strong TH 17/TH 1 T-cell responses. J Allergy Clin. Immunol. 2011 (127).787-794.
  9. Schäkel K, von Kietzell M, Hänsel A, Ebling A, Schulze L, Haase M, Semmler C, Sarfati M, Barclay NO, Randolph GJ, Meurer M, Rieber EP: Human 6-sulfo LacNAc-expressing dendritic cells are principal producers of early interleukin-12 and are controlled by erythrocytes. Immunity. 2006 (24):767-777.
  10. Schäkel K, Kannagi R, Goto Y, Mitsuaoka C, Zwirner J, Soruri A, Kniep B, Rieber EP: 6-sulfoLacNAc, a novel carbohydrate modification of PSGL-1, defines an inflammatory type of human dendritic cells. Immunity. 2002 (17) 289-301.