Cited by 280Cellular Mechanics and InteractionsImmune Response and InflammationNF-κB Signaling Pathways

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Spatial confinement downsizes the inflammatory response of macrophages

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Jain, Nikhil, Vogel, Viola·2018·Nature Materials

DOI 10.1038/s41563-018-0190-6PMC PMC6615903

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Abstract

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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Authors: Jain, N., & Vogel, V.
Affiliations: ETH Zurich (CH)
Corresponding author: Jain, Nikhil
ORCID: Jain, Nikhil
Vogel, Viola
Venue: Nature Materials
Publisher: Springer Science and Business Media LLC
Published: 2018-10-22
Volume: 17
Issue: 12
Pages: 1134-1144
ISSN: 1476-1122 (ISSN-L)
1476-4660
DOI: 10.1038/s41563-018-0190-6
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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Spatial confinement downsizes the inflammatory response of macrophages

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