PMID- 25340460
OWN - NLM
STAT- MEDLINE
DCOM- 20160201
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 10
DP  - 2014
TI  - Fc gamma receptor IIb on GM-CSF macrophages controls immune complex mediated 
      inhibition of inflammatory signals.
PG  - e110966
LID - 10.1371/journal.pone.0110966 [doi]
LID - e110966
AB  - BACKGROUND: In rheumatoid arthritis (RA) macrophages play a major role in 
      amplifying synovial inflammation. Important activating signals are those induced 
      by Toll-like receptor (TLR) ligands and by activated T cells. The balance between 
      activating and inhibitory Fc gamma receptors (FcgammaRs) on macrophages might be 
      crucial in modulating these inflammatory responses. The purpose of this study was 
      to determine FcgammaR expression on pro- and anti-inflammatory macrophages (gmMphi and 
      mMphi, respectively) and identify functional consequences on immune complex uptake 
      and macrophage activation. METHODS: Human monocytes were isolated and 
      differentiated into gmMphi and mMphi. A full FcgammaR characterization of both macrophage 
      subtypes was performed and uptake of fluorescent immune complexes (ICs) was 
      determined. FcgammaRIIb isoforms were determined by qPCR. Macrophages were stimulated 
      via different TLRs or cytokine activated T cells in the presence or absence of 
      ICs and cytokine production was determined. Blocking studies were performed to 
      look into the pathways involved. RESULTS: mMphi expressed high levels of the 
      activating FcgammaRIIa and FcgammaRIII and low levels of the inhibitory FcgammaRIIb, while 
      the FcgammaR balance on gmMphi was shifted towards the inhibitory FcgammaRIIb. This was 
      accompanied by a clear increase in FcgammaRIIb1 mRNA expression in gmMphi. This 
      resulted in higher IC uptake by mMphi compared to gmMphi. Furthermore, FcgammaR-mediated 
      stimulation of gmMphi inhibited TLR2, 3, 4 and 7/8 mediated cytokine production via 
      FcgammaRIIb and PI3K signaling. In addition, gmMphi but not mMphi produced TNFalpha upon 
      co-culture with cytokine activated T cells, which was reduced by IC binding to 
      FcgammaRIIb. The latter was dependent on PI3K signaling and COX2. CONCLUSIONS: FcgammaR 
      expression patterns on gmMphi and mMphi are significantly different, which translates 
      in clear functional differences further substantiating FcgammaRIIb as an interesting 
      target for inflammation control in RA and other autoimmune/inflammatory diseases.
FAU - Santegoets, Kim C M
AU  - Santegoets KC
AD  - Department of Rheumatology & Clinical Immunology, University Medical Center 
      Utrecht, Utrecht, the Netherlands; Laboratory of Translational Immunology, 
      Department of Immunology, University Medical Center Utrecht, Utrecht, the 
      Netherlands; Department of Rheumatology, Radboud university medical center, 
      Nijmegen, the Netherlands.
FAU - Wenink, Mark H
AU  - Wenink MH
AD  - Department of Rheumatology & Clinical Immunology, University Medical Center 
      Utrecht, Utrecht, the Netherlands; Laboratory of Translational Immunology, 
      Department of Immunology, University Medical Center Utrecht, Utrecht, the 
      Netherlands; Department of Rheumatology, Radboud university medical center, 
      Nijmegen, the Netherlands.
FAU - van den Berg, Wim B
AU  - van den Berg WB
AD  - Department of Rheumatology, Radboud university medical center, Nijmegen, the 
      Netherlands.
FAU - Radstake, Timothy R D J
AU  - Radstake TR
AD  - Department of Rheumatology & Clinical Immunology, University Medical Center 
      Utrecht, Utrecht, the Netherlands; Laboratory of Translational Immunology, 
      Department of Immunology, University Medical Center Utrecht, Utrecht, the 
      Netherlands; Department of Rheumatology, Radboud university medical center, 
      Nijmegen, the Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141023
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antigen-Antibody Complex)
RN  - 0 (Cytokines)
RN  - 0 (Fc gamma receptor IIB)
RN  - 0 (Ligands)
RN  - 0 (Receptors, IgG)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 130068-27-8 (Interleukin-10)
RN  - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
SB  - IM
MH  - Antigen-Antibody Complex/immunology
MH  - Coculture Techniques
MH  - Cytokines/metabolism
MH  - Granulocyte-Macrophage Colony-Stimulating Factor/*metabolism
MH  - Humans
MH  - Inflammation/*metabolism
MH  - Interleukin-10/metabolism
MH  - Ligands
MH  - Lymphocyte Activation
MH  - Macrophages/cytology/*immunology/metabolism
MH  - Microscopy, Fluorescence
MH  - Monocytes/cytology/metabolism
MH  - Phagocytosis
MH  - Phenotype
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Protein Binding
MH  - Receptors, IgG/*metabolism
MH  - Signal Transduction
MH  - T-Lymphocytes/cytology
MH  - Tumor Necrosis Factor-alpha/metabolism
PMC - PMC4207781
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/10/24 06:00
MHDA- 2016/02/02 06:00
PMCR- 2014/10/23
CRDT- 2014/10/24 06:00
PHST- 2014/05/28 00:00 [received]
PHST- 2014/09/26 00:00 [accepted]
PHST- 2014/10/24 06:00 [entrez]
PHST- 2014/10/24 06:00 [pubmed]
PHST- 2016/02/02 06:00 [medline]
PHST- 2014/10/23 00:00 [pmc-release]
AID - PONE-D-14-21854 [pii]
AID - 10.1371/journal.pone.0110966 [doi]
PST - epublish
SO  - PLoS One. 2014 Oct 23;9(10):e110966. doi: 10.1371/journal.pone.0110966. 
      eCollection 2014.