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Characterizing the anti-inflammatory and tissue protective actions of a novel Annexin A1 peptide.

Abstract Inflammation in now appreciated to be at the centre of may diseases that affect Western civilization. Current therapeutics for managing these conditions may interfere with the host response leading to immune suppression. We recently developed an annexin (Anx) A1-derived peptide, coined CR-AnxA12-50, which displays potent pro-resolving and tissue protective actions. Herein, we designed a novel peptide using CR-AnxA12-50 as a template that was significantly more resistant to neutrophil-mediated degradation. This peptide, termed CR-AnxA12-48, retained high affinity and specificity to the pro-resolving Lipoxin A4 receptor (ALX) with an IC50 of ~20nM. CR-AnxA12-48 dose dependently (100fM-10nM) promoted the efferocytosis of apoptotic neutrophils, an action that was mediated by the murine orthologue of human ALX. The neutrophil-directed actions were also retained with human primary cells were CR-AnxA12-48 reduced human neutrophil recruitment to activated endothelial cells at concentrations as low as 100 pM. This protective action was mediated by human ALX, since incubation of neutrophils with an anti-ALX antibody reversed this anti-inflammatory actions of CR-AnxA12-48. Administration of this peptide to mice during dermal inflammation led to a significant and dose dependent decrease in neutrophil recruitment. This reduction in neutrophil numbers was more pronounced than that displayed by the parent peptide CR-AnxA12-50. CR-AnxA12-48 was also cardioprotecitve reducing infarct size and systemic chemokine (C-C motif) ligand 5 concentration following ischemia reperfusion injury. These findings identify CR-AnxA12-48 as a new ALX agonist that regulates phagocyte responses and displays tissue-protective actions.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title plos one
Publication Year Start




PMID- 28407017
OWN - NLM
STAT- MEDLINE
DA  - 20170413
DCOM- 20170420
LR  - 20170420
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 4
DP  - 2017
TI  - Characterizing the anti-inflammatory and tissue protective actions of a novel
      Annexin A1 peptide.
PG  - e0175786
LID - 10.1371/journal.pone.0175786 [doi]
AB  - Inflammation in now appreciated to be at the centre of may diseases that affect
      Western civilization. Current therapeutics for managing these conditions may
      interfere with the host response leading to immune suppression. We recently
      developed an annexin (Anx) A1-derived peptide, coined CR-AnxA12-50, which
      displays potent pro-resolving and tissue protective actions. Herein, we designed 
      a novel peptide using CR-AnxA12-50 as a template that was significantly more
      resistant to neutrophil-mediated degradation. This peptide, termed CR-AnxA12-48, 
      retained high affinity and specificity to the pro-resolving Lipoxin A4 receptor
      (ALX) with an IC50 of ~20nM. CR-AnxA12-48 dose dependently (100fM-10nM) promoted 
      the efferocytosis of apoptotic neutrophils, an action that was mediated by the
      murine orthologue of human ALX. The neutrophil-directed actions were also
      retained with human primary cells were CR-AnxA12-48 reduced human neutrophil
      recruitment to activated endothelial cells at concentrations as low as 100 pM.
      This protective action was mediated by human ALX, since incubation of neutrophils
      with an anti-ALX antibody reversed this anti-inflammatory actions of
      CR-AnxA12-48. Administration of this peptide to mice during dermal inflammation
      led to a significant and dose dependent decrease in neutrophil recruitment. This 
      reduction in neutrophil numbers was more pronounced than that displayed by the
      parent peptide CR-AnxA12-50. CR-AnxA12-48 was also cardioprotecitve reducing
      infarct size and systemic chemokine (C-C motif) ligand 5 concentration following 
      ischemia reperfusion injury. These findings identify CR-AnxA12-48 as a new ALX
      agonist that regulates phagocyte responses and displays tissue-protective
      actions.
FAU - Perretti, Mauro
AU  - Perretti M
AD  - The William Harvey Research Institute, Barts and The London School of Medicine,
      Queen Mary University of London, Charterhouse Square, London, United Kingdom.
FAU - Di Filippo, Clara
AU  - Di Filippo C
AD  - Department of Experimental Medicine, Second University of Naples, Naples, Italy.
FAU - D'Amico, Michele
AU  - D'Amico M
AD  - Department of Experimental Medicine, Second University of Naples, Naples, Italy.
FAU - Dalli, Jesmond
AU  - Dalli J
AUID- ORCID: http://orcid.org/0000-0001-6328-3640
AD  - The William Harvey Research Institute, Barts and The London School of Medicine,
      Queen Mary University of London, Charterhouse Square, London, United Kingdom.
LA  - eng
PT  - Journal Article
DEP - 20170413
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Annexin A1)
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Cardiotonic Agents)
RN  - 0 (HSH2D protein, human)
RN  - 0 (Peptides)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/metabolism
MH  - Animals
MH  - Annexin A1/*chemistry
MH  - Anti-Inflammatory Agents/*administration & dosage/pharmacology
MH  - Cardiotonic Agents/*administration & dosage/pharmacology
MH  - Disease Models, Animal
MH  - Human Umbilical Vein Endothelial Cells
MH  - Humans
MH  - Inflammation/*drug therapy/etiology/immunology/metabolism
MH  - Male
MH  - Mice
MH  - Myocardial Reperfusion Injury/*prevention & control
MH  - Neutrophils/drug effects
MH  - Peptides/*administration & dosage/pharmacology
MH  - Phagocytes/drug effects
EDAT- 2017/04/14 06:00
MHDA- 2017/04/21 06:00
CRDT- 2017/04/14 06:00
PHST- 2017/02/22 [received]
PHST- 2017/03/31 [accepted]
AID - 10.1371/journal.pone.0175786 [doi]
AID - PONE-D-17-07241 [pii]
PST - epublish
SO  - PLoS One. 2017 Apr 13;12(4):e0175786. doi: 10.1371/journal.pone.0175786.
      eCollection 2017.

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