PMID- 27509208
OWN - NLM
STAT- MEDLINE
DCOM- 20170822
LR  - 20220129
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 11
IP  - 8
DP  - 2016
TI  - Netrin-1 Reduces Monocyte and Macrophage Chemotaxis towards the Complement 
      Component C5a.
PG  - e0160685
LID - 10.1371/journal.pone.0160685 [doi]
LID - e0160685
AB  - Netrin-1, acting at its cognate receptor UNC5b, has been previously demonstrated 
      to inhibit CC chemokine-induced immune cell migration. In line with this, we 
      found that netrin-1 was able to inhibit CCL2-induced migration of bone marrow 
      derived macrophages (BMDMs). However, whether netrin-1 is capable of inhibiting 
      chemotaxis to a broader range of chemoattractants remains largely unexplored. As 
      our initial experiments demonstrated that RAW264.7 and BMDMs expressed high 
      levels of C5a receptor 1 (C5aR1) on their surface, we aimed to determine the 
      effect of netrin-1 exposure on monocyte/macrophage cell migration induced by C5a, 
      a complement peptide that plays a major role in multiple inflammatory 
      pathologies. Treatment of RAW264.7 macrophages, BMDMs and human monocytes with 
      netrin-1 inhibited their chemotaxis towards C5a, as measured using two different 
      real-time methods. This inhibitory effect was found to be dependent on netrin-1 
      receptor signalling, as an UNC5b blocking antibody was able to reverse netrin-1 
      inhibition of C5a induced BMDM migration. Treatment of BMDMs with netrin-1 had no 
      effect on C5aR1 proximal signalling events, as surface C5aR1 expression, 
      internalisation and intracellular Ca2+ release following C5aR1 ligation remained 
      unaffected after netrin-1 exposure. We next examined receptor distal events that 
      occur following C5aR1 activation, but found that netrin-1 was unable to inhibit 
      C5a induced phosphorylation of ERK1/2, Akt and p38, pathways important for 
      cellular migration. Furthermore, netrin-1 treatment had no effect on BMDM 
      cytoskeletal rearrangement following C5a stimulation as determined by microscopy 
      and real-time electrical impedance sensing. Taken together these data highlight 
      that netrin-1 inhibits monocyte and macrophage cell migration, but that the 
      mechanism behind this effect remains unresolved. Nevertheless, netrin-1 and its 
      cognate receptors warrant further investigation as they may represent a potential 
      avenue for the development of novel anti-inflammatory therapeutics.
FAU - Taylor, Lewis
AU  - Taylor L
AUID- ORCID: 0000-0003-4622-9890
AD  - Sir William Dunn School of Pathology, University of Oxford, Oxford, United 
      Kingdom.
FAU - Brodermann, Maximillian Hugo
AU  - Brodermann MH
AD  - Sir William Dunn School of Pathology, University of Oxford, Oxford, United 
      Kingdom.
FAU - McCaffary, David
AU  - McCaffary D
AD  - Sir William Dunn School of Pathology, University of Oxford, Oxford, United 
      Kingdom.
FAU - Iqbal, Asif Jilani
AU  - Iqbal AJ
AD  - Sir William Dunn School of Pathology, University of Oxford, Oxford, United 
      Kingdom.
FAU - Greaves, David R
AU  - Greaves DR
AD  - Sir William Dunn School of Pathology, University of Oxford, Oxford, United 
      Kingdom.
LA  - eng
GR  - RG/15/10/31485/BHF_/British Heart Foundation/United Kingdom
PT  - Journal Article
DEP - 20160810
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (C5ar1 protein, mouse)
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Immunologic Factors)
RN  - 0 (NTN1 protein, human)
RN  - 0 (Nerve Growth Factors)
RN  - 0 (Ntn1 protein, mouse)
RN  - 0 (Receptor, Anaphylatoxin C5a)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 158651-98-0 (Netrin-1)
RN  - 80295-54-1 (Complement C5a)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Calcium/metabolism
MH  - Cell Line
MH  - Chemokine CCL2/genetics/metabolism
MH  - Chemotaxis/drug effects/*physiology
MH  - Complement C5a/*metabolism
MH  - Humans
MH  - Immunologic Factors/pharmacology
MH  - Macrophages/drug effects/*physiology
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Monocytes/drug effects/physiology
MH  - Nerve Growth Factors/chemistry/metabolism/*pharmacology
MH  - Netrin-1
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Receptor, Anaphylatoxin C5a/metabolism
MH  - Signal Transduction/drug effects
MH  - Tumor Suppressor Proteins/chemistry/metabolism/*pharmacology
PMC - PMC4980032
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2016/08/11 06:00
MHDA- 2017/08/23 06:00
PMCR- 2016/08/10
CRDT- 2016/08/11 06:00
PHST- 2016/04/05 00:00 [received]
PHST- 2016/07/24 00:00 [accepted]
PHST- 2016/08/11 06:00 [entrez]
PHST- 2016/08/11 06:00 [pubmed]
PHST- 2017/08/23 06:00 [medline]
PHST- 2016/08/10 00:00 [pmc-release]
AID - PONE-D-16-13727 [pii]
AID - 10.1371/journal.pone.0160685 [doi]
PST - epublish
SO  - PLoS One. 2016 Aug 10;11(8):e0160685. doi: 10.1371/journal.pone.0160685. 
      eCollection 2016.