PMID- 30524196
OWN - NLM
STAT- MEDLINE
DCOM- 20190219
LR  - 20190320
IS  - 1466-1861 (Electronic)
IS  - 0962-9351 (Print)
IS  - 0962-9351 (Linking)
VI  - 2018
DP  - 2018
TI  - Amphiregulin Regulates Phagocytosis-Induced Cell Death in Monocytes via EGFR and 
      Matrix Metalloproteinases.
PG  - 4310419
LID - 10.1155/2018/4310419 [doi]
LID - 4310419
AB  - Neonates are highly susceptible to microbial infections which is partially 
      attributable to fundamental phenotypic and functional differences between 
      effector cells of the adult and neonatal immune system. The resolution of the 
      inflammation is essential to return to tissue homeostasis, but given that various 
      neonatal diseases, such as periventricular leukomalacia, necrotizing 
      enterocolitis, or bronchopulmonary dysplasia, are characterized by sustained 
      inflammation, newborns seem predisposed to a dysregulation of the inflammatory 
      response. Targeted apoptosis of effector cells is generally known to control the 
      length and extent of the inflammation, and previous studies have demonstrated 
      that phagocytosis-induced cell death (PICD), a special type of apoptosis in 
      phagocytic immune cells, is less frequently triggered in neonatal monocytes than 
      in adult monocytes. We concluded that a rescue of monocyte PICD could be a 
      potential therapeutic approach to target sustained inflammation in neonates. The 
      EGFR ligand amphiregulin (AREG) is shed in response to bacterial infection and 
      was shown to mediate cellular apoptosis resistance. We hypothesized that AREG 
      might contribute to the reduced PICD of neonatal monocytes by affecting apoptosis 
      signaling. In this study, we have examined a cascade of signaling events involved 
      in extrinsic apoptosis by using a well-established in vitro E. coli infection 
      model in monocytes from human peripheral blood (PBMO) and cord blood (CBMO). We 
      found that CBMO shows remarkably higher pro-AREG surface expression as well as 
      soluble AREG levels in response to infection as compared to PBMO. AREG increases 
      intracellular MMP-2 and MMP-9 levels and induces cleavage of membrane-bound FasL 
      through engagement with the EGF receptor. Our results demonstrate that loss of 
      AREG rescues PICD in CBMO to the level comparable to adult monocytes. These 
      findings identify AREG as a potential target for the prevention of prolonged 
      inflammation in neonates.
FAU - Platen, Christopher
AU  - Platen C
AUID- ORCID: 0000-0003-4063-7789
AD  - Department of Neonatology, University Children's Hospital, Aachen, Germany.
FAU - Dreschers, Stephan
AU  - Dreschers S
AUID- ORCID: 0000-0003-2527-3673
AD  - Department of Neonatology, University Children's Hospital, Aachen, Germany.
FAU - Reiss, Lucy Kathleen
AU  - Reiss LK
AUID- ORCID: 0000-0001-9567-3328
AD  - Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen 
      University, Aachen, Germany.
FAU - Wappler, Jessica
AU  - Wappler J
AUID- ORCID: 0000-0003-1431-9613
AD  - Molecular Tumor Biology, Department of General, Visceral and Transplantation 
      Surgery, University Hospital, Aachen, Germany.
FAU - Orlikowsky, Thorsten W
AU  - Orlikowsky TW
AUID- ORCID: 0000-0001-7123-0629
AD  - Department of Neonatology, University Children's Hospital, Aachen, Germany.
LA  - eng
PT  - Journal Article
DEP - 20181104
PL  - United States
TA  - Mediators Inflamm
JT  - Mediators of inflammation
JID - 9209001
RN  - 0 (Amphiregulin)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
RN  - EC 3.4.24.24 (Matrix Metalloproteinase 2)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
SB  - IM
MH  - Amphiregulin/genetics/*metabolism
MH  - Apoptosis/genetics/physiology
MH  - Cell Death/genetics/*physiology
MH  - Cells, Cultured
MH  - Enzyme-Linked Immunosorbent Assay
MH  - ErbB Receptors/genetics/metabolism
MH  - Escherichia coli/pathogenicity
MH  - Flow Cytometry
MH  - Humans
MH  - Matrix Metalloproteinase 2/genetics/metabolism
MH  - Matrix Metalloproteinase 9/genetics/metabolism
MH  - Matrix Metalloproteinases/genetics/metabolism
MH  - Monocytes/*cytology/*metabolism
MH  - Phagocytosis/genetics/*physiology
PMC - PMC6247478
EDAT- 2018/12/14 06:00
MHDA- 2019/03/21 06:00
PMCR- 2018/11/04
CRDT- 2018/12/08 06:00
PHST- 2018/04/24 00:00 [received]
PHST- 2018/07/26 00:00 [revised]
PHST- 2018/08/29 00:00 [accepted]
PHST- 2018/12/08 06:00 [entrez]
PHST- 2018/12/14 06:00 [pubmed]
PHST- 2019/03/21 06:00 [medline]
PHST- 2018/11/04 00:00 [pmc-release]
AID - 10.1155/2018/4310419 [doi]
PST - epublish
SO  - Mediators Inflamm. 2018 Nov 4;2018:4310419. doi: 10.1155/2018/4310419. 
      eCollection 2018.