TNFα-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury

Manish Mittal, Chinnaswamy Tiruppathi, Saroj Nepal, You Yang Zhao, Dagmara Grzych, Dheeraj Soni, Darwin J. Prockop*, Asrar B. Malik

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

97 Scopus citations


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 antiinflammatory 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.

Original languageEnglish (US)
Pages (from-to)E8151-E8158
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number50
StatePublished - Dec 13 2016


  • Biological sciences
  • Immunology
  • Inflammation acute lung injury
  • Medical sciences

ASJC Scopus subject areas

  • General


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