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WNT5A induces profibrotic activation of human macrophages via pSTAT3
Emily A Morris1, Chen-Yu Wang1, Chanhyuk Park1
1Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
Objectives:
WNT5A is a non-canonical WNT ligand that is overexpressed in autoimmune systemic sclerosis (SSc). While the pathogenic effects of WNT5A have been established in SSc fibroblasts, its contribution to profibrotic SSc macrophage activation is unknown. The goal of this study was to determine the effects of WNT5A on fibrotic macrophage activation.
Methods:
Human monocyte-derived macrophages were cultured in the presence of recombinant WNT5A and assessed for changes in immunophenotype, STAT3 phosphorylation, and cytokine secretion. The ability of WNT5A-treated macrophages to induce healthy donor and SSc patient fibroblast activation was evaluated in the presence or absence of macrophage-specific pSTAT3 inhibition.
Results:
WNT5A significantly increased surface levels of the profibrotic markers CD163 and CD16, and the secretion of CCL2, TNF, IL-10 and IL-6, which are characteristic of profibrotic SSc macrophage activation. WNT5A also increased the percentage of pSTAT3+ macrophages as well as the overall STAT3 phosphorylation levels, which we have shown in prior work are basally activated in SSc macrophages. Moreover, STAT3 inhibition of WNT5A-treated macrophages significantly attenuated their ability to induce activation of SSc patient but not healthy donor fibroblasts.
Conclusion:
Collectively, these results indicate that WNT5A mediates profibrotic macrophage activation through a pSTAT3-dependent mechanism. As SSc fibroblasts secrete elevated levels of WNT5A, our experiments suggest that, in addition to autocrine functions, paracrine WNT5A may also contribute to pathological macrophage activation in SSc.
Insights
WNT5A promotes fibrotic macrophage activation in systemic sclerosis (SSc) via STAT3 signaling. This finding suggests WNT5A contributes to SSc pathogenesis through paracrine effects on macrophages.
Area of Science:
- Immunology
- Cell Biology
- Rheumatology
Background:
- WNT5A is overexpressed in systemic sclerosis (SSc).
- WNT5A's role in SSc fibroblast activation is known, but its effect on macrophages is unclear.
- Understanding WNT5A's impact on macrophages is crucial for SSc research.
Purpose of the Study:
- To investigate the effects of WNT5A on fibrotic macrophage activation.
- To determine the mechanism by which WNT5A influences macrophage phenotype and function.
Main Methods:
- Human monocyte-derived macrophages were treated with WNT5A.
- Immunophenotype, STAT3 phosphorylation, and cytokine secretion were analyzed.
- Macrophage-induced fibroblast activation was assessed with and without STAT3 inhibition.
Main Results:
- WNT5A increased profibrotic markers (CD163, CD16) and cytokine secretion (CCL2, TNF, IL-10, IL-6).
- WNT5A enhanced STAT3 phosphorylation in macrophages.
- WNT5A-activated macrophages induced SSc fibroblast activation, dependent on STAT3.
Conclusions:
- WNT5A drives profibrotic macrophage activation through a STAT3-dependent pathway.
- Paracrine WNT5A from SSc fibroblasts may contribute to macrophage activation in SSc.
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