Spatial confinement downsizes the inflammatory response of macrophages. Issue 12 (December 2018)

• Record Type: Journal Article
• Authors: Jain, Nikhil; Vogel, Viola
• Is Part Of: Nature materials. Volume 17:Issue 12(2018)
• Page Start: 1134
• Page End: 1144
• Publication Date: 2018-12
• Subjects: Materials science -- Periodicals; Materials -- Technological innovations -- Periodicals; Materials -- Periodicals; 620.1105
• DOI: 10.1038/s41563-018-0190-6
• Languages: English
• ISSNs: 1476-1122

Abstract

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 (biomarkersIL-6, CXCL9, IL-1β, andiNOS ) 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.