Spatial confinement downsizes the inflammatory response of macrophages

Nat Mater. 2018 Dec;17(12):1134-1144. doi: 10.1038/s41563-018-0190-6. Epub 2018 Oct 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Cytokines / metabolism
  • Epigenesis, Genetic / drug effects
  • Histone Deacetylases / metabolism
  • Inflammation / immunology
  • Lipopolysaccharides / pharmacology
  • Macrophages / cytology*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • RAW 264.7 Cells
  • Signal Transduction / drug effects
  • Transcription, Genetic / drug effects


  • Actins
  • Cytokines
  • Lipopolysaccharides
  • Histone Deacetylases
  • histone deacetylase 3