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Spatial confinement downsizes the inflammatory response of macrophages
Open accessAbstract
Macrophages respond to chemical/metabolic and physical stimuli, but their effects cannot be readily decoupled in vivo during pro-inflammatory activation. Here, we show that preventing macrophage spreading by spatial confinement, as imposed by micropatterning, microporous substrates or cell crowding, suppresses late lipopolysaccharide (LPS)-activated transcriptional programs (biomarkers IL-6, CXCL9, IL-1β, and iNOS) 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. 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-κB and IRF3 signalling and hence the expression of early LPS-responsive genes were marginally affected by confinement. These findings have broad implications in the context of mechanobiology, inflammation and immunology, as well as in tissue engineering and regenerative medicine.Physical confinement of macrophages is shown to down-regulate pro-inflammatory gene transcription, lowering pro-inflammatory macrophage activation and phagocytic potential.
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“IFN-γ and TNF-α induce activation of Ml macrophages to trigger a respiratory burst, release reactive oxygen species, secrete TNF-α and IL-12, induce iNOS, and upregulate expression of programmed death-ligand 1 (PD-L1) (Jain and Vogel, 2018;Tan et al., 2019).”
From Nanosilver alleviates foreign body reaction and facilitates wound repair by regulating macrophage polarization (2023) · cites this paper as Jain and Vogel, 2018
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Metadata
- Authors
- Jain, N., & Vogel, V.
- Affiliations
- ETH Zurich (CH)
- Corresponding author
- Jain, Nikhil
- Venue
- Nature Materials
- Published
- 2018-10-22
- Volume
- 17
- Issue
- 12
- Pages
- 1134-1144
- ISSN
- 1476-1122 (ISSN-L)
- 1476-4660
- PMC
- PMC6615903
- OpenAlex
- W2897232908
- Semantic Scholar
- 1ac0e557d3aa67ca54c6e9b0d8a6b4d14e856299
- Cited by
- 271
- References
- 65
- Citations by year
- 2026: 27 · 2025: 39 · 2024: 45 · 2023: 38 · 2022: 47 · 2021: 42 · 2020: 20 · 2019: 12 · 2018: 1
- FWCI
- 10.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Materials (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (156931)
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (U54DK106857)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- macrophage inflammation, spatial confinement, micropatterning, cell crowding, lipopolysaccharide, mechanotransduction, chromatin condensation, epigenetic regulation, HDAC3, H3K36 dimethylation, actin polymerization, MRTF-A, SRF, inflammatory cytokines, phagocytosis, mechanobiology, TLR4 signaling
- MeSH terms
- RAW 264.7 Cells, Histone Deacetylase 3, Actins, Animals, Histone Deacetylases, Inflammation, Lipopolysaccharides, Macrophages, Transcription, Genetic, Signal Transduction, Cytokines, Epigenesis, Genetic, Mice
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