The role of the inflammasome in joint homeostasis and the development of osteoarthritis
Final Report Abstract
Aim of this studies was to characterize inflammasome function in non-myeloid cells, in particular in chondrocytes. We first determined the presence of the essential components of the Nlrp3- inflammasome in primary murine chondrocytes. Furthermore, the capability to respond to known inflammasome stimuli has been tested and we could show that chondrocytes are capable to produce active IL-1β. Current literature implicates this cytokine in the progression of Osteoarthritis. Therefore, we investigated whether physiological relevant risk factors for developing Osteoarthritis are able to induce inflammasome activation in myeloid cells as well as chondrocytes. Subsequently, we were the first to demonstrate that osmotic stress can indeed induce inflammasome activation dependent on NLRP3. Thus this study provides novel mechanistic insights into a possible involvement of inflammasomes and IL-1 signaling in the development and progression of Osteoarthritis. In a separate part of this Fellowship we investigated the role of the inflammasome adaptor ASC in keratinocytes and its role in the progression of epithelial skin cancer. Surprisingly, we identified two diametrically opposing functions of ASC in cancer progression depending on whether it is expressed in tumor infiltrating myeloid cells or tumor cells (keratinocytes). ASC drives tumor-genesis when expressed in myeloid cells through its involvement in inflammasome activation. In keratinocytes, however, it serves as a tumor suppressor, independently of its inflammasome function. One possible mechanism for its tumor suppressive role might be its involvement in p53 activation. Furthermore, ASC expression is down-regulated in human cutaneous SCC. Thus, this study describes ASC as a drugable target for the treatment of epithelial skin cancer.
Publications
- Activation of the NLRP3 inflammasome by Nanoparticles. 2nd Eurocrystal meeting, 9th-11th March 2011 Paris, France
Drexler S.K.
- Activation of the NLRP3 inflammasome by Nanoparticles. Annual Retreat Karolinska Institute, 23th-25th March 2011 Stockholm, Sweden
Drexler S.K.
- The role of the inflammasome in non-myeloid cells. EULAR 2011, 25th-28th May 2011 London, UK
Drexler S.K.
- The role of the inflammasome in osteoarthritis. Autoinflammatory days 2011, 12th-13th December 2011 Padova, Italy
Drexler S.K.
- Contrasting, cell type-specific, functions of the inflammasome adaptor ASC as tumor promoter and suppressor in epithelial skin cancer. PNAS 2012 Oct 22. [Epub ahead of print]
Drexler S.K., Bonsignore L., Masin M., Tardivel A., Schneider P., Gross O, Tschopp J., Yazdi A.S.
- Inflammasome activators induce interleukin-1α secretion via distinct pathways with differential requirement for the protease function of caspase-1. Immunity 2012 Mar 23;36(3):388-400
Groß O., Yazdi A.S., van Netten-Thomas C., Heinz L.X., Guarda G., Quadroni M., Drexler S.K., Tschopp J.
(See online at https://doi.org/10.1016/j.immuni.2012.01.018) - The role of IL-1α in crystal induced inflammation. Advances in Targeted Therapies, 27th of March to 1st of April 2012 Stresa, Italy
Drexler S.K.
