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Proteinase-activated receptor-2 modulates human macrophage differentiation and effector function
Rachael Steven1, Anne Crilly, John C Lockhart
11Centre for Musculoskeletal Science, School of Science, University of the West of Scotland, Paisley, UK.
Abstract:
Proteinase-activated receptor-2 (PAR-2) was shown to influence immune regulation; however, its role in human macrophage subset development and function has not been addressed. Here, PAR-2 expression and activation was investigated on granulocyte macrophage (GM)-CSF(M1) and macrophage (M)-CSF(M2) macrophages. In both macrophages, the PAR-2-activating peptide, SLIGKV, increased PAR-2 expression and regulated TNF-α and IL-10 secretion in a manner similar to LPS. In addition, HLA-DR on M1 cells also increased. Monocytes matured to an M1 phenotype in the presence of SLIGKV had reduced cell area, and released less TNF-α after LPS challenge compared with vehicle (P < 0.05, n = 3). Cells matured to an M2 phenotype with SLIGKV also had a reduced cell area and made significantly more TNF-α after LPS exposure compared to vehicle (P < 0.05, n = 3) with reduced IL-10 secretion (P < 0.05, n = 3). Thus, PAR-2 activation on macrophage subsets regulates HLA-DR and PAR-2 surface expression, and drives cytokine production. In contrast, PAR-2 activation during M1 or M2 maturation induces altered cell morphology and skewing of phenotype, as evidenced by cytokine secretion. These data suggest a complex role for PAR-2 in macrophage biology and may have implications for macrophage-driven disease in which proteinase-rich environments can influence the immune process directly.
Insights
Proteinase-activated receptor-2 (PAR-2) influences human macrophage subsets, regulating cytokine production and cell morphology. PAR-2 activation during maturation alters M1 and M2 macrophage phenotypes, impacting immune responses.
Area of Science:
- Immunology
- Cell Biology
- Molecular Medicine
Background:
- Proteinase-activated receptor-2 (PAR-2) is implicated in immune regulation.
- The specific role of PAR-2 in human macrophage subset development and function remains unclear.
Purpose of the Study:
- To investigate PAR-2 expression and activation in human granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived M1 and macrophage colony-stimulating factor (M-CSF)-derived M2 macrophages.
- To determine the effects of PAR-2 activation on macrophage phenotype, cytokine secretion, and morphology.
Main Methods:
- Human monocytes were differentiated into M1 and M2 macrophages.
- PAR-2 activation was induced using the peptide SLIGKV.
- PAR-2 expression, HLA-DR levels, cell morphology, and cytokine secretion (TNF-α, IL-10) were analyzed.
Main Results:
- SLIGKV increased PAR-2 expression and regulated TNF-α and IL-10 secretion in both M1 and M2 macrophages, similar to LPS.
- PAR-2 activation increased HLA-DR on M1 cells.
- PAR-2 activation during M1 or M2 maturation altered cell morphology and skewed cytokine secretion profiles, impacting TNF-α and IL-10 release.
Conclusions:
- PAR-2 activation directly influences macrophage subset surface marker expression and cytokine production.
- PAR-2 plays a complex role in macrophage biology, affecting both mature cell function and differentiation processes.
- These findings suggest implications for diseases involving proteinase-rich environments and macrophage-driven immune responses.
