The role of the inflammasome in joint homeostasis and the development of osteoarthritis

• Applicant: Dr. Stefan Karl Drexler
• Subject Area: Cell Biology
• Term: from 2010 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 190432129

Inflammasomes are cytosolic multi-protein complexes that can proteolytically activate caspase- 1. Activated caspase-1 is needed for the maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18. In the past decade there has been tremendous progress in our knowledge of inflammasome function and IL-1 signaling, mainly in cells of the innate immune system, such as monocytes, macrophages, neutrophils and dendritic cells. As non-immune cells, including keratinocytes, synovial cells or astrocytes, can form an interface between the body and the environment or a defined compartment (brain, joint) they are important guardians for the detection of danger signals and the consecutive initiation of an inflammatory response. They are present in anatomical compartments that are less accessible to myeloid cells and thus can fulfill tasks usually performed by residential macrophages. The studies proposed here will elucidate the role of inflammasomes in non-immune cells, in particular chondrocytes, the cells responsible for joint integrity. Ultimately, this will lead to a better understanding whether inflammasome activation in tissue resident cells plays a part in the induction and progression of inflammatory and/or tissue destructive conditions, such as osteoarthritis (OA). Aim 1: This project will define the expression and function of the inflammasome in non-myeloid cells. In particular primary articular chondrocytes, the cell type responsible for cartilage repair in the joint, will be studied. Aim 2: In this context the role of the inflammasome and IL-1 signaling in tissue homeostasis will be examined. As a model, this study will define the possible involvement of the inflammasome in the progression of OA, where IL-1β has been defined as a major factor in disease progression. This will in the long term potentially define new targets for the therapy of OA.

• DFG Programme: Research Fellowships
• International Connection: Switzerland
• Host: Professor Dr. Jürg Tschopp (†)