Cytokine biology, synovitis and inflammation

Head: Dr. rer. nat. Silke Frey

We investigate the function of inflammatory messenger substances (cytokines) in autoimmune diseases such as psoriasis and rheumatoid arthritis. An excess reaction against the body's own tissues (skin or joint) leads to severe inflammation and joint destruction. Using mouse models as well as human tissues, the expression, function and dysregulation of cytokines will be determined. The knowledge gained from this will provide new approaches for successful therapies for inflammatory arthritis.

 

The focus of our research group is to identify immunological mechanisms that control the conversion of rheumatic inflammation, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), towards its resolution. Approximately 30% of patients suffering from the inflammatory skin disease psoriasis develop joint involvement, PsA. In this case, in addition to the typical skin manifestation (heavily scaling, red plaques), joint inflammation is also present. The severity of the disease can be very variable. Currently, there is no cure for these chronic inflammatory skin and joint diseases. Due to an excess reaction against the body's own tissues, RA and PsA lead to severe inflammation, and if left untreated, to joint destruction and severe limitations as well as suffering for the patients. A research focus of our group is interleukin (IL)-36, a member of the IL-1 cytokine family, which is significantly involved in the chronic skin inflammation psoriasis. Thus, dysregulation of IL-36 cytokines is thought to lead to an accumulation of neutrophil granulocytes as well as macrophages in the inflammatory tissue, resulting in increased proliferation of fibroblasts and ultimately joint damage.

As a further focus, the group is investigating effects of cytokine-dependent signaling on the regulation of bone formation in RA using JAK/STAT inhibitors. Using murine arthritis and psoriasis models as well as human tissues and cells, the expression, function and disease-relevant dysregulation of cytokines will be determined. Based on these studies, our goal is to develop new concepts and to provide a basis for the investigation of future therapeutics.

  • Regulation of cytokines in PsA pathogenesis.

It is hypothesized that misregulation of the IL-36 cytokine family leads to an accumulation of immune cells, such as neutrophil granulocytes, as well as macrophages in the inflammatory tissue, resulting in increased proliferation of fibroblasts and ultimately joint damage. For this purpose, the regulation of cytokines and the presence of different immune cell populations in inflamed skin and bone will be investigated. For these studies, we have two inducible mouse models (mannan and tumor necrosis factor α (ihTNFtg)) that develop PsA similar to humans. These models are reversible and allow studies both in the phase of inflammation and in its resolution. This project will also investigate the influence of other inflammatory mediators such as peroxidases and proteases as a possible cause of resolution and chronification of inflammatory arthritis in vitro and in vivo.

  • Function of IL-36 in B-lymphoid cells in inflammatory arthritis.

IL-36 is expressed in the synovium of PsA patients, especially by B and plasma cells. In addition, IL-36 activates synovial fibroblasts (FLS) of the synovium and induces the production of cytokines such as IL-6 and chemokines by binding to the IL-36 receptor. This project aims to further analyze the IL-36-mediated interplay between B-lymphoid cells and FLS. These findings will provide us with information on the formation and maintenance of an inflammatory niche in bone.

  • Secretion of IL-36

Despite the assumption that IL-36 family cytokines function extracellularly, it is unclear how, and if, IL-36 is secreted. We are therefore investigating the secretion of IL-36α using various IL-36 constructs and inhibitors. Using an established cell system, it was confirmed that IL-36α cannot be released via the classical secretion pathway due to the lack of a signal peptide. Preliminary studies indicate that IL-36α is externalized via the involvement of secretory lysosomes and/or intracellular endosomes.

  • Effects of cytokine-dependent signaling on bone formation.

The JAK/STAT pathway is a central signaling pathway that mediates the transmission of inflammatory signals to the interior of almost all body cells. The relevance for the JAK/STAT signaling pathway for bone metabolism has been shown, for example, in the STAT1 knockout mice, which has higher bone density than control mice. In addition, inflammatory cytokines such as IL-6 that activate the JAK/STAT pathway are known to affect bone metabolism and impair bone formation. JAK inhibitors, in turn, inhibit this same signal transduction. This project will investigate the impact of inhibition of the JAK/STAT pathway on bone formation in RA/PsA patients and in mouse models.

 

Silke FreyResearch group leader
Marc RingerScientific doctoral candidate
Alexander FinsterMedical doctoral candidate
Burak AksoyMaster student

 

Deutsche Forschungsgemeinschaft (DFG)
CRC 1181 "Modification of cytokines by myeloperoxidase activity and (un)known mediators in resolution of psoriatic disease." (2019-2023)

ELAN-Programm, Friedrich-Alexander University Erlangen-Nürnberg
"The role of IL-36α in the B cell and the influence on the
malignant B cell degeneration" (2012-2013)

"Characterization of high pressure induced stress signals and their impact on tumor cell immunogenicity." (2008-2009)

 

  1. Frey S, Sticht H, Wilsmann-Theis D, Gerschütz A, Wolf K, Löhr S, Haskamp S, Frey B, Hahn M, Ekici AB, Uebe S, Thiel C, Reis A, Burkhardt H, Behrens F, Köhm M, Rech J, Schett G, Assmann G, Kingo K, Kõks S, Mössner R, Prinz JC, Oji V, Schulz P, Muñoz LE, Kremer AE, Wenzel J, Hüffmeier U. (2020) Rare Loss-of-Function Mutation in SERPINA3 in Generalized Pustular Psoriasis. J Invest Dermatol. 140(7):1451-1455.e13.
  2. Adam S, Simon N, Steffen U, Andes FT, Scholtysek C, Müller DIH, Weidner D, Andreev D, Kleyer A, Culemann S, Hahn M, Schett G, Krönke G, Frey S*, Hueber AJ*. (2020) JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function. Sci Transl Med. 12(530):eaay4447. *equally contributed
  3. Schmitt V, Hahn M, Kästele V, Wagner O, Wiendl M, Derer A, Taddeo A, Hahne S, Radbruch A, Jäck HM, Schuh W, Mielenz D, Gay S, Schett G, Hueber AJ, Frey S. (2017) Interleukin-36 receptor mediates the crosstalk between plasma cells and synovial fibroblasts. Eur J Immunol. 47(12):2101-2112.
  4. Kurow O, Frey B, Schuster L, Schmitt V, Adam S, Hahn M, Gilchrist D, McInnes IB, Wirtz S, Gaipl US, Krönke G, Schett G, Frey S*, Hueber AJ*. (2017) Full Length Interleukin 33 Aggravates Radiation-Induced Skin Reaction. Front Immunol. 8:722. *equally contributed
  5. Derer A, Groetsch B, Harre U, Böhm C, Towne J, Schett G, Frey S*, Hueber AJ*. (2014) Blockade of IL-36 receptor signaling does not prevent from TNF-induced arthritis. PLoS One. 9(8):e101954. *equally contributed
  6. Frey S, Derer A, Messbacher ME, Baeten DL, Bugatti S, Montecucco C, Schett G, Hueber AJ. (2013) The novel cytokine interleukin-36α is expressed in psoriatic and rheumatoid arthritis synovium.Ann Rheum Dis. 72(9):1569-74.
  7. Lang VR, Mielenz D, Neubert K, Böhm C, Schett G, Jäck HM, Voll RE*, Meister S*. (2010) The early marginal zone B cell-initiated T-independent type 2 response resists the proteasome inhibitor bortezomib.J Immunol. 185(9):5637-47. *equally contributed
  8. Meister S, Frey B, Lang VR, Gaipl US, Schett G, Schlötzer-Schrehardt U, Voll RE. (2010) Calcium channel blocker verapamil enhances endoplasmic reticulum stress and cell death induced by proteasome inhibition in myeloma cells. Neoplasia. 12(7):550-61.
  9. Neubert K, Meister S, Moser K, Weisel F, Maseda D, Amann K, Wiethe C, Winkler TH, Kalden JR, Manz RA, Voll RE. (2008) The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat Med. 14(7):748-55.
  10. Meister S, Schubert U, Neubert K, Herrmann K, Burger R, Gramatzki M, Hahn S, Schreiber S, Wilhelm S, Herrmann M, Jäck HM, Voll RE. (2007) Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Res. 67(4):1783-92.


PubMed publication list of Dr. Silke Frey

 

 

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