Genetic deletion of TNFR2 augments inflammatory response and blunts satellite-cell-mediated recovery response in a hind limb ischemia model

Sharath P. Sasi, Layla Rahimi, Xinhua Yan, Marcy Silver, Gangjian Qin, Douglas W. Losordo, Raj Kishore, David A. Goukassian*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

We have previously shown that TNF-tumor necrosis factor receptor-2/p75 (TNFR2/p75) signaling plays a critical role in ischemia-induced neovascularization in skeletal muscle and heart tissues. To determine the role of TNF-TNFR2/p75 signaling in ischemia-induced inflammation and muscle regeneration, we subjected wild-type (WT) and TNFR2/p75 knockout (p75KO) mice to hind limb ischemia (HLI) surgery. Ischemia induced significant and long-lasting inflammation associated with considerable decrease in satellite-cell activation in p75KO muscle tissue up to 10 d after HLI surgery. To determine the possible additive negative roles of tissue aging and the absence of TNFR2/p75, either in the tissue or in the bone marrow (BM), we generated 2 chimeric BM transplantation (BMT) models where both young green fluorescent protein (GFP)-positive p75KO and WT BM-derived cells were transplanted into adult p75KO mice. HLI surgery was performed 1 mo after BMT, after confirming complete engraftment of the recipient BM with GFP donor cells. In adult p75KO with the WT-BMT, proliferative (Ki67+) cells were detected only by d 28 and were exclusively GFP+, suggesting significantly delayed contribution of young WT-BM cell to adult p75KO ischemic tissue recovery. No GFP+young p75KO BM cells survived in adult p75KO tissue, signifying the additive negative roles of tissue aging combined with decreased/absent TNFR2/p75 signaling in postischemic recovery.

Original languageEnglish (US)
Pages (from-to)1208-1219
Number of pages12
JournalFASEB Journal
Volume29
Issue number4
DOIs
StatePublished - Apr 1 2015

Keywords

  • Apoptosis
  • Muscle regeneration
  • Proliferation
  • TNF-TNFR2/p75 signaling

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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