Marlous Dillingh has a background in biomedical sciences. She is currently in training as a clinical pharmacologist at the Centre for Human Drug Research, Leiden, The Netherlands. Her main expertise is the integration of inflammation/immunology and pharmacology, applied in early phase clinical drug development, which is the focus of her PhD education.
Inflammasomes are multiprotein complexes inducing pro-inflammatory cytokine production in response to infection and tissue injury. The end product of inflammasome activity is caspase-1-induced release of effector molecules such as IL-1 β and IL-18 from immune cells. Despite the common outcome, the variety of triggers that initiate inflammasome activity is large, and moreover eight different inflammasome subclasses have been described. The inflammasome is a potential therapeutic target for chronic inflammatory diseases such as chronic kidney disease and atherosclerosis. To test the effects of future inflammasome-targeted therapies, an ‘inflammasome bioassay’ is highly warranted. The inflammasome’s capacity to sense widely divergent ligands, and the diversity in inflammasome subclasses, indicates that a single bioassay may not be sufficient to assess potential inflammasome-modulating effects of new compounds. Therefore, we developed a set of bioassays inducing inflammasome activity, so-called ‘inflammasome challenges’. Variables that were explored included matrix/cells (whole blood, PBMCs, THP1), triggers, incubation time (3-24 hours), dose-response relationship, single trigger versus immune cell priming followed by a second trigger, and inflammasome end products (IL-1β, IL-18). We successfully developed a set of inflammasome challenges, comprising inflammasome activation by LPS alone and by different triggers after LPS priming (extracellular ATP, aluminium hydroxide, cholesterol crystals, oligomeric β-amyloid). The short-term LPS inflammasome challenge was demonstrated to be sensitive to modulation of inflammasome activity, as assessed with a direct caspase-1 inhibitor. These inflammasome challenges can be applied in translational drug development as readout measures for inflammasome inhibition, and moreover will provide mechanistic insight in regulation of inflammasome activity.
Baochi Liu received his Ph.D. from Zhengzhou University in 2007. He received his B.S.in 1983. He has many Peer-reviewed Publications in reputed journals. His research interest includes general surgery, surgery infection and trauma. He is currently working as a Director and Professor in Department of Surgery, Shanghai Publical Health Clinical Center Affiliated to Fudan University, Shanghai, China.
Objective: Fractures can trigger an immune response that disturbs the homeostasis of osteoblast and osteoclast through the production and release of cytokines and their receptors. The purpose of our study was to investigate CCR4 as potential cellular components of the osteoimmune system's response to an in vivo model of bone injury. The absence of CCR4 influences the fate of other responder cells in proliferation, differentiation, matrix production, and ultimate callus formation. Methods: Tibia fractures were induced in 50 CCR4-deficient mice and 50 control C57BL/6 mice. Examinations of radiographs, basic histology, mechanical testing, flow cytometry, immunohistochemical, as well as enzyme-linked immunosorbent assay for the effector cytokines interleukin-2 (IL-2), interferon, and IL-6 were performed. Results: Animals deficient in CCR4 cells revealed less mature histologic elements and quantitative decreases in the expression of major bone (bone sialoprotein) and cartilage (type II collagen) matrix proteins and in the expression of bone morphogenetic protein 2 at a critical reparative phase. Moreover, only CCR4-deficient animals had an increase in the osteoprogenitor antiproliferative cytokines IL-6 and interferon at the reparative phase. The result was improved stability at the repair site and an overall superior biomechanical strength in CCR4-deficient mice compared with controls. Conclusion: The evidence for a role of CCR4 in the context of skeletal injury indicated the importance of the immune system's influence on bone biology, which is associated with the field of osteoimmunology, and offers a potential molecular platform from which to develop essential therapeutic strategies.