Seminar: “Mechano-Immunology” Exploring physical drivers of macrophage specification and activation by microenvironment-niche engineering and epigenomics
| Dates: | 21 February 2019 |
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| Times: | 11:00 - 12:00 |
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| What is it: | Seminar |
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| Organiser: | Faculty of Biology, Medicine and Health |
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| Who is it for: | University staff, Current University students |
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| Speaker: | Nikhil Jain |
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Macrophages are unique in the sense that they perform their function under a variety of different physical environments. Macrophage-like microglia cells in the brain sense low ECM stiffness, within the vasculature, blood flow can critically affect macrophage survival and function, and macrophage like-osteoclasts are constantly subjected to mechanical loading in bone. Even though a large amount of available literature suggesting chemical/metabolic signals regulating macrophage tissue-specification and function is available, all these studies have so far not been able to clarify how macrophages acquire tissue-specific phenotypic and functional states. Further, even though it is now known that during the loss of cellular and tissue homeostasis and the onset of pathological conditions (fibrotic/atherosclerotic/cancerous), the physical properties of a tissue including stiffness, architecture and cellular composition changes dramatically, it is poorly understood how these changes in the physical parameters of tissues co-regulate the pro-inflammatory and pro-healing activation of macrophages. While the conventional immunology community broadly focuses on the chemical/metabolic niche regulation, the possible regulatory role of physical niches of macrophages has so far not been considered in the design and interpretation of previous experiments and published reports. Understanding the mechanisms how physical properties of the microenvironment can tune macrophages specification and activation is highly significant to better understand how macrophages drive the progression of diseases and vice-versa to learn how materials can be engineered to tune their phenotypes.
I will show how macrophage spatial confinement, as imposed by micropatterning, 3D microporous substrates or cell crowding, suppresses late lipopolysaccharide (LPS)-activated transcriptional programs by mechanomodulating chromatin compaction and epigenetic alterations (HDAC3 levels and H3K36-dimethylation). Mechanistically, confinement reduces actin polymerization, thereby lowers the LPS-stimulated nuclear translocation of MRTF-A. This lowers the activity of the MRTF-A–SRF complex and subsequently downregulates the inflammatory response, as confirmed by chromatin immunoprecipitation coupled with quantitative PCR and RNA sequencing analysis and complemented with super resolution microscopy. Confinement thus downregulates pro-inflammatory cytokine secretion and, well before any activation processes, the phagocytic potential of macrophages. Contrarily, early events, including activation of the LPS receptor TLR4, and downstream NF-? B and IRF3 signaling and hence the expression of early LPS-responsive genes were marginally affected by confinement. These findings have broad implications in the context of inflammation and immunology, as well as in tissue engineering and regenerative medicine.
Speaker
Nikhil Jain
Organisation: ETH Zurich
Travel and Contact Information
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1.006
AV Hill Building
Manchester
