The alarmin S100A8/S100A9 is a key regulator of monocyte activation and homing

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Phagocytes are fast migrating cells throw-out the body and are important for the pathogen defense. Therefore these cells have to migrate and transmigrate to sites of infection in a coordinated way. The cellular dynamics underlying inflammatory activation of monocytes are regulated by signaling pathways that involve changes in intracellular calcium, GTPase activation and specific protein kinases. The aim of this project is to unravel the function of the major calcium binding protein complex S100A8/S100A9, using Lifeact Hoxb8 monocytes from wild-type and S100A9 knock-out mice. S100A8/S100A9 heterodimers are well studied alarmins involved in inflammatory processes by triggering TLR-4 dependent pathways. Moreover, these proteins are known to induce neutrophil adhesion by activation of β2 integrins.
However, mechanisms to keep these cells in the resting state are far less understood.
Interestingly, we found major alterations in the cytoskeletal dynamics and morphology of S100A9 knock-out cells. Already in the resting state, S100A9 knock-out monocytes showed faster migration and transmigration rates, reduced adhesion properties, lower traction forces and an elevated activation level of Rho GTPases compared to wild-type monocytes. Surprisingly after stimulation with chemokines, only the wild-type cells were able to respond and increase their migratory activity whereas the S100A9 knock-out cells seem to be already pre-activated and remained unaffected by chemokine stimulation. Substitution of missing extracellular S100A8/A9 in S100A9 knock-out cells reversed the phenotype again to a resting state. Our findings suggest that the extracellular S100A8/S100A9 control monocyte dynamics through the binding to the novel S100 receptor CD69 on monocytes.

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