Abstract
Prior exposure to microenvironmental signals could fundamentally change the response of macrophages to subsequent stimuli. It is believed that T helper-2 (Th2)-cell-type cytokine interleukin-4 (IL-4) and Toll-like receptor (TLR) ligand-activated transcriptional programs mutually antagonize each other, and no remarkable convergence has been identified between them. In contrast, here, we show that IL-4-polarized macrophages established a hyperinflammatory gene expression program upon lipopolysaccharide (LPS) exposure. This phenomenon, which we termed extended synergy, was supported by IL-4-directed epigenomic remodeling, LPS-activated NF-κB-p65 cistrome expansion, and increased enhancer activity. The EGR2 transcription factor contributed to the extended synergy in a macrophage-subtype-specific manner. Consequently, the previously alternatively polarized macrophages produced increased amounts of immune-modulatory factors both in vitro and in vivo in a murine Th2 cell-type airway inflammation model upon LPS exposure. Our findings establish that IL-4-induced epigenetic reprogramming is responsible for the development of inflammatory hyperresponsiveness to TLR activation and contributes to lung pathologies.
Original language | English (US) |
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Pages (from-to) | 2006-2026.e6 |
Journal | Immunity |
Volume | 55 |
Issue number | 11 |
DOIs | |
State | Published - Nov 8 2022 |
Keywords
- EGR2
- IL-4
- LPS
- STAT6
- Th2-type airway inflammation
- epigenetic reprogramming
- inflammation
- macrophage
- synergistic gene activation
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Infectious Diseases