PMID- 26264566
OWN - NLM
STAT- MEDLINE
DCOM- 20170105
LR  - 20170106
IS  - 1932-846X (Electronic)
IS  - 1932-8451 (Linking)
VI  - 76
IP  - 5
DP  - 2016 May
TI  - Nitric oxide regulates antagonistically phagocytic and neurite outgrowth 
      inhibiting capacities of microglia.
PG  - 566-84
LID - 10.1002/dneu.22333 [doi]
AB  - Traumatic injury or the pathogenesis of some neurological disorders is 
      accompanied by inflammatory cellular mechanisms, mainly resulting from the 
      activation of central nervous system (CNS) resident microglia. Under inflammatory 
      conditions, microglia up-regulate the inducible isoform of NOS (iNOS), leading to 
      the production of high concentrations of the radical molecule nitric oxide (NO). 
      At the onset of inflammation, high levels of microglial-derived NO may serve as a 
      cellular defense mechanism helping to clear the damaged tissue and combat 
      infection of the CNS by invading pathogens. However, the excessive overproduction 
      of NO by activated microglia has been suggested to govern the 
      inflammation-mediated neuronal loss causing eventually complete 
      neurodegeneration. Here, we investigated how NO influences phagocytosis of 
      neuronal debris by BV-2 microglia, and how neurite outgrowth of human NT2 model 
      neurons is affected by microglial-derived NO. The presence of NO greatly 
      increased microglial phagocytic capacity in a model of acute inflammation 
      comprising lipopolysaccharide (LPS)-activated microglia and apoptotic neurons. 
      Chemical manipulations suggested that NO up-regulates phagocytosis independently 
      of the sGC/cGMP pathway. Using a transwell system, we showed that reactive 
      microglia inhibit neurite outgrowth of human neurons via the generation of large 
      amounts of NO over effective distances in the millimeter range. Application of a 
      NOS blocker prevented the LPS-induced NO production, totally reversed the 
      inhibitory effect of microglia on neurite outgrowth, but reduced the engulfment 
      of neuronal debris. Our results indicate that a rather simple notion of treating 
      excessive inflammation in the CNS by NO synthesis blocking agents has to consider 
      functionally antagonistic microglial cell responses during pharmaceutic therapy.
CI  - (c) 2015 Wiley Periodicals, Inc.
FAU - Scheiblich, Hannah
AU  - Scheiblich H
AD  - Division of Cell Biology, University of Veterinary Medicine Hannover, Germany.
FAU - Bicker, Gerd
AU  - Bicker G
AD  - Division of Cell Biology, University of Veterinary Medicine Hannover, Germany.
AD  - Center for Systems Neuroscience Hannover, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150821
PL  - United States
TA  - Dev Neurobiol
JT  - Developmental neurobiology
JID - 101300215
RN  - 0 (Lipopolysaccharides)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 4.6.1.2 (Guanylate Cyclase)
RN  - H2D2X058MU (Cyclic GMP)
SB  - IM
MH  - Animals
MH  - Apoptosis/physiology
MH  - Cell Line
MH  - Coculture Techniques
MH  - Cyclic GMP/metabolism
MH  - Guanylate Cyclase/metabolism
MH  - Humans
MH  - Inflammation/*metabolism
MH  - Lipopolysaccharides
MH  - Mice
MH  - Microglia/immunology/*physiology
MH  - Neurites/*physiology
MH  - Neuroimmunomodulation
MH  - *Neuronal Outgrowth
MH  - Nitric Oxide/*metabolism
MH  - Phagocytes/*physiology
MH  - *Phagocytosis
MH  - Signal Transduction
OTO - NOTNLM
OT  - BV-2 microglia
OT  - NT2 model neurons
OT  - cGMP
OT  - growth cone
OT  - nitric oxide synthase
EDAT- 2015/08/13 06:00
MHDA- 2017/01/06 06:00
CRDT- 2015/08/13 06:00
PHST- 2015/06/18 00:00 [received]
PHST- 2015/07/28 00:00 [revised]
PHST- 2015/08/04 00:00 [accepted]
PHST- 2015/08/13 06:00 [entrez]
PHST- 2015/08/13 06:00 [pubmed]
PHST- 2017/01/06 06:00 [medline]
AID - 10.1002/dneu.22333 [doi]
PST - ppublish
SO  - Dev Neurobiol. 2016 May;76(5):566-84. doi: 10.1002/dneu.22333. Epub 2015 Aug 21.