报告题目: Mechano-Immunology of Macrophage Polarization
报告人职务：Post-Doctoral Associate, Department of Health, Science and Technology, ETH Zurich, Switzerland
摘要:Tissue-resident macrophages encounter physical stimuli and spatial constraints, both from extracellular matrix stiffness, architecture, and composition and from neighbouring cells. During inflammation circulating monocytes (M0) get activated into a spectrum of states, from the pro-inflammatory (M1) all the way to the pro-regenerative (M2) states. They thereby switch their transcriptional profiles, gene expression and hence functional outputs, which results in an upregulated secretion of pro-inflammatory or pro-regenerative cytokines for macrophages ranging from M1 to M2 phenotypes, respectively. Even though macrophages are often residing or operating in spatial confinements, rather little is known whether and how cell confinement might tune their transcriptional control, epigenetic modifications, functional outputs and hence activation. While most of what we know today about mechanobiological phenomena associated with cell confinement have been learned from the study of fibroblasts and epithelial cells, comparatively little is known about immune cells especially during activation. Given the importance of macrophages in orchestrating healing, tissue regeneration, but also in various inflammatory diseases, I asked how the confinement of macrophages affects their activation process.
I show that macrophage confinement, as imposed by micropatterning, 3D-microporous substrates or cell crowding, suppresses late LPS-activated transcriptional programs by mechano-modulating chromatin compaction and altering HDAC3 levels and H3K36-dimethylation. Mechanistically, confinement reduces actin-polymerization, lowers nuclear translocation of MRTF-A, and hence MRTF-A-SRF complex activity as required for a prolonged inflammatory response, as confirmed by ChIP-qPCR and RNA-Seq analysis. Confinement thus downregulates pro-inflammatory cytokine secretion and phagocytic potential of macrophages. Contrary, early events including activation of the LPS receptor TLR4, NF-B and IRF3 signalling and hence the expression of early LPS-responsive genes was marginally affected by the confinement. These findings have broad implications in the context of mechanobiology, inflammation, and immunology, as well as in tissue engineering and regenerative medicine.
报告人简介：Post-Doctoral Associate, Department of Health, Science and Technology, ETH Zurich, Switzerland.