PMID- 23209800
OWN - NLM
STAT- MEDLINE
DCOM- 20130522
LR  - 20230313
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 11
DP  - 2012
TI  - TLR2 and TLR4 mediate differential responses to limb ischemia through 
      MyD88-dependent and independent pathways.
PG  - e50654
LID - 10.1371/journal.pone.0050654 [doi]
LID - e50654
AB  - INTRODUCTION: The danger signal HMGB1 is released from ischemic myocytes, and 
      mediates angiogenesis in the setting of hindlimb ischemia. HMGB1 is a ligand for 
      innate immune receptors TLR2 and TLR4. While both TLR2 and TLR4 signal through 
      myeloid differentiation factor 88 (MyD88), TLR4 also uniquely signals through 
      TIR-domain-containing adapter-inducing interferon-beta (TRIF). We hypothesize that 
      TLR2 and TLR4 mediate ischemic myocyte regeneration and angiogenesis in a manner 
      that is dependent on MyD88 signaling. METHODS: Mice deficient in TLR2, TLR4, 
      MyD88 and TRIF underwent femoral artery ligation in the right hindlimb. Laser 
      Doppler perfusion imaging was used to assess the initial degree of ischemia and 
      the extent of perfusion recovery. Muscle regeneration, necrosis and fat 
      replacement at 2 weeks post-ligation were assessed histologically and vascular 
      density was quantified by immunostaining. In vitro, endothelial tube formation 
      was evaluated in matrigel in the setting of TLR2 and TLR4 antagonism. RESULTS: 
      While control and TLR4 KO mice demonstrated prominent muscle regeneration, both 
      TLR2 KO and TRIF KO mice exhibited marked necrosis with significant inflammatory 
      cell infiltrate. However, MyD88 KO mice had a minimal response to the ischemic 
      insult with little evidence of injury. This observation could not be explained by 
      differences in perfusion recovery which was similar at two weeks in all the 
      strains of mice. TLR2 KO mice demonstrated abnormal vessel morphology compared to 
      other strains and impaired tube formation in vitro. DISCUSSION: TLR2 and TRIF 
      signaling are necessary for muscle regeneration after ischemia while MyD88 may 
      instead mediate muscle injury. The absence of TLR4 did not affect muscle 
      responses to ischemia. TLR4 may mediate inflammatory responses through MyD88 that 
      are exaggerated in the absence of TLR2. Additionally, the actions of TLR4 through 
      TRIF may promote regenerative responses that are required for recovery from 
      muscle ischemia.
FAU - Sachdev, Ulka
AU  - Sachdev U
AD  - Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania, United States of America.
FAU - Cui, Xiangdong
AU  - Cui X
FAU - McEnaney, Ryan
AU  - McEnaney R
FAU - Wang, Tian
AU  - Wang T
FAU - Benabou, Kelly
AU  - Benabou K
FAU - Tzeng, Edith
AU  - Tzeng E
LA  - eng
GR  - UL1 RR024153/RR/NCRR NIH HHS/United States
GR  - T32 HL098036/HL/NHLBI NIH HHS/United States
GR  - UL1TR000005/TR/NCATS NIH HHS/United States
GR  - UL1RR024153/RR/NCRR NIH HHS/United States
GR  - I01 BX000635/BX/BLRD VA/United States
GR  - UL1 TR000005/TR/NCATS NIH HHS/United States
GR  - T32HL098036/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20121129
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Myeloid Differentiation Factor 88)
RN  - 0 (Toll-Like Receptor 2)
RN  - 0 (Toll-Like Receptor 4)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Hindlimb/metabolism/pathology
MH  - Humans
MH  - Ischemia/genetics/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Muscle, Skeletal/metabolism/pathology
MH  - Myeloid Differentiation Factor 88/genetics/*metabolism
MH  - Necrosis/metabolism/pathology
MH  - Neovascularization, Pathologic/metabolism/pathology
MH  - Signal Transduction/genetics/physiology
MH  - Toll-Like Receptor 2/genetics/*metabolism
MH  - Toll-Like Receptor 4/genetics/*metabolism
PMC - PMC3510193
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/12/05 06:00
MHDA- 2013/05/23 06:00
PMCR- 2012/11/29
CRDT- 2012/12/05 06:00
PHST- 2012/04/30 00:00 [received]
PHST- 2012/10/24 00:00 [accepted]
PHST- 2012/12/05 06:00 [entrez]
PHST- 2012/12/05 06:00 [pubmed]
PHST- 2013/05/23 06:00 [medline]
PHST- 2012/11/29 00:00 [pmc-release]
AID - PONE-D-12-12249 [pii]
AID - 10.1371/journal.pone.0050654 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(11):e50654. doi: 10.1371/journal.pone.0050654. Epub 2012 Nov 29.