TNF-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury. Conference Paper uri icon

abstract

  • TNF-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-B activation. TSG6 also prevented the expression of proinflammatory proteins (iNOS, IL-6, TNF, IL-1, 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-B signaling and STAT1 and STAT3 activation.

published proceedings

  • Proc Natl Acad Sci U S A

altmetric score

  • 34.25

author list (cited authors)

  • Mittal, M., Tiruppathi, C., Nepal, S., Zhao, Y., Grzych, D., Soni, D., Prockop, D. J., & Malik, A. B.

citation count

  • 96

complete list of authors

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

publication date

  • December 2016