title: Genetic deletion of TNFR2 augments inflammatory response and blunts satellite-cell-mediated recovery response in a hind limb ischemia model.
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.
authors.affiliation: Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts, USA;
authors.forename: Sharath P
authors.initials: SP
authors.lastname: Sasi
authors.affiliation: Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts, USA;
authors.forename: Layla
authors.initials: L
authors.lastname: Rahimi
authors.affiliation: Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts, USA; Tufts University School of Medicine, Boston, Massachusetts, USA;
authors.forename: Xinhua
authors.initials: X
authors.lastname: Yan
authors.affiliation: Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts, USA;
authors.forename: Marcy
authors.initials: M
authors.lastname: Silver
authors.affiliation: Feinberg Cardiovascular Institute, Feinberg School of Medicine Northwestern University, Chicago, Illinois, USA; and.
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.affiliation: Feinberg Cardiovascular Institute, Feinberg School of Medicine Northwestern University, Chicago, Illinois, USA; and.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Temple University, Philadelphia, Pennsylvania, USA.
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.affiliation: Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts, USA; Tufts University School of Medicine, Boston, Massachusetts, USA; david.goukassian@tufts.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Goukassian
mesh_terms: D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics; D006614:Hindlimb / Q000098:blood supply; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D007511:Ischemia / Q000473:pathology* / Q000503:physiopathology* / Q000628:therapy; D008264:Macrophages / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D020556:Neutrophil Infiltration; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000473:pathology* / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins
keywords: TNF-TNFR2/p75 signaling; apoptosis; muscle regeneration; proliferation