ukb.uni-bonn.de

The Pathophysiology of Platelet-derived Cyokines

We are interested in the cellular interactions that drive innate immunity in host resistance to infection and autoinflammatory diseases. More specifically, we are interested in how the interaction of platelets with different immune cells modulate their function and drive innate immunity. There are approximately one trillion platelets circulating in the blood, a quantity that outnumbers by tenfold all other leukocytes in the vasculature. These small non-nucleated cells circulate through the vascular system reaching all organs in the body. Although it has been known for quite a while that platelets produce and secrete different cytokines and chemokines, their specific contribution to host defence against infection and to the development of auto inflammatory diseases is largely unknown. With funding from the European Research Council, our group aims to decipher the contributions of platelets and of platelet-derived factors to host resistance to bacterial, virus infection and to sterile inflammation.

 

Figure 1 - During the initial steps of vascular inflammation damaged endothelial cells release IL‐1α, a pre-formed alarmin. IL-1α binds to the IL-1 receptor (IL-1R) on surrounding fibroblasts and epithelial cells, causing them to release chemokines. Platelets are one of the first cells to reach the inflammatory tissue site, where they exert antimicrobial activities. Stocks of pre-made IL-1 cytokines (IL-1α and IL-1β) released from activated platelets, amplify IL-1 inflammatory signals. These cytokines attract and facilitate the passage of circulating blood neutrophils into the tissue inflammatory site. IL-1-stimulated surrounding endothelial cells express adhesion molecules, such as ICAM1, to which circulating neutrophils adhere to, and enter the tissue via diapedesis. Neutrophil-platelet interaction is crucial for neutrophil invasion of the tissue. The number of tissue infiltrating neutrophils rapidly increases and the presence of local IL-1 prolongs their survival, exacerbating tissue damage.

Interaction of platelets and immune cells: new targets for checkpoint immunotherapies in cancer

There is growing evidence that inflammation fuels cancer development and metastasis. Although the idea of harnessing immune cells to fight cancer isn’t new, only recently enough clinical data has accumulated to demonstrate what a game-changer cancer immunotherapy can be. Nevertheless, there is still a big fraction of patients that do not respond to immunotherapy, and immunotherapy is only effective in a subset of cancers. Thus, unraveling the complex interplay of immune and cancer cells in the tumor microenvironment might provide important insights that will improve existing therapies or will help for the development of new therapies. Blood platelets have essential roles in initiating and sustaining inflammation either by directly contributing to production of pro-inflammatory factors, or by interacting with immune cells and enhancing their pro-inflammatory activity. Platelets, are not only crucial for the migration of immune cells (neutrophils and monocytes) from the blood vessels into the tumor microenviroment, but are also a rich source of many pro-inflammatory cytokines and chemokines which have well established roles in cancer. In this project funded by the Brigitte und Dr. Konstanze Wegener-Stiftung, we will investigate in different ways the interaction of platelets with immune cells to explore new checkpoint therapies for cancer.

Confocal imaging of Platelet and Neutrophil interaction

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