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TNFα-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury
Manish Mittal1, Chinnaswamy Tiruppathi1, Saroj Nepal1
1Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL 60612.
Abstract:
TNFα-stimulated gene-6 (TSG6), a 30-kDa protein generated by activated macrophages, modulates inflammation; however, its mechanism of action and role in the activation of macrophages are not fully understood. Here we observed markedly augmented LPS-induced inflammatory lung injury and mortality in TSG6-/- mice compared with WT (TSG6+/+) mice. Treatment of mice with intratracheal instillation of TSG6 prevented LPS-induced lung injury and neutrophil sequestration, and increased survival in mice. We found that TSG6 inhibited the association of TLR4 with MyD88, thereby suppressing NF-κB activation. TSG6 also prevented the expression of proinflammatory proteins (iNOS, IL-6, TNFα, IL-1β, and CXCL1) while increasing the expression of anti-inflammatory proteins (CD206, Chi3l3, IL-4, and IL-10) in macrophages. This shift was associated with suppressed activation of proinflammatory transcription factors STAT1 and STAT3. In addition, we observed that LPS itself up-regulated the expression of TSG6 in TSG6+/+ mice, suggesting an autocrine role for TSG6 in transitioning macrophages. Thus, TSG6 functions by converting macrophages from a proinflammatory to an anti-inflammatory phenotype secondary to suppression of TLR4/NF-κB signaling and STAT1 and STAT3 activation.
Insights
Tumor necrosis factor-alpha-stimulated gene-6 (TSG6) protein reduces inflammatory lung injury by shifting macrophages to an anti-inflammatory state. TSG6 suppresses key signaling pathways, promoting healing and increasing survival rates.
Area of Science:
- Immunology
- Molecular Biology
Background:
- Tumor necrosis factor-alpha-stimulated gene-6 (TSG6) is a macrophage-derived protein involved in inflammation.
- Its precise mechanism of action and role in macrophage activation remain unclear.
Purpose of the Study:
- To investigate the role of TSG6 in lipopolysaccharide (LPS)-induced inflammatory lung injury.
- To elucidate the molecular mechanisms by which TSG6 modulates macrophage phenotype and inflammatory responses.
Main Methods:
- Comparison of LPS-induced lung injury and mortality in TSG6 knockout (TSG6-/-) and wild-type (TSG6+/+) mice.
- Treatment with intratracheal TSG6 in mice subjected to LPS challenge.
- Analysis of Toll-like receptor 4 (TLR4)/MyD88 association, NF-κB activation, and expression of pro- and anti-inflammatory mediators in macrophages.
- Assessment of STAT1 and STAT3 activation.
Main Results:
- TSG6-/- mice exhibited exacerbated LPS-induced lung injury and mortality.
- TSG6 treatment protected against lung injury, reduced neutrophil infiltration, and improved survival.
- TSG6 inhibited TLR4-MyD88 association, suppressed NF-κB activation, and decreased proinflammatory protein expression.
- TSG6 promoted anti-inflammatory protein expression and shifted macrophage phenotype, suppressing STAT1 and STAT3 activation.
- LPS induced TSG6 expression in wild-type mice, suggesting an autocrine role.
Conclusions:
- TSG6 plays a critical protective role in inflammatory lung injury.
- TSG6 converts macrophages from a proinflammatory to an anti-inflammatory phenotype by inhibiting TLR4/NF-κB signaling and STAT1/STAT3 activation.
- TSG6 has therapeutic potential for inflammatory lung diseases.
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