PMID- 29792190
OWN - NLM
STAT- MEDLINE
DCOM- 20190408
LR  - 20190816
IS  - 1742-2094 (Electronic)
IS  - 1742-2094 (Linking)
VI  - 15
IP  - 1
DP  - 2018 May 23
TI  - Novel insights into neuroinflammation: bacterial lipopolysaccharide, tumor 
      necrosis factor alpha, and Ureaplasma species differentially modulate atypical 
      chemokine receptor 3 responses in human brain microvascular endothelial cells.
PG  - 156
LID - 10.1186/s12974-018-1170-0 [doi]
LID - 156
AB  - BACKGROUND: Atypical chemokine receptor 3 (ACKR3, synonym CXCR7) is increasingly 
      considered relevant in neuroinflammatory conditions, in which its upregulation 
      contributes to compromised endothelial barrier function and may ultimately allow 
      inflammatory brain injury. While an impact of ACKR3 has been recognized in 
      several neurological autoimmune diseases, neuroinflammation may also result from 
      infectious agents, including Ureaplasma species (spp.). Although commonly 
      regarded as commensals of the adult urogenital tract, Ureaplasma spp. may cause 
      invasive infections in immunocompromised adults as well as in neonates and appear 
      to be relevant pathogens in neonatal meningitis. Nonetheless, clinical and in 
      vitro data on Ureaplasma-induced inflammation are scarce. METHODS: We established 
      a cell culture model of Ureaplasma meningitis, aiming to analyze ACKR3 variances 
      as a possible pathomechanism in Ureaplasma-associated neuroinflammation. 
      Non-immortalized human brain microvascular endothelial cells (HBMEC) were exposed 
      to bacterial lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha), and 
      native as well as LPS-primed HBMEC were cultured with Ureaplasma urealyticum 
      serovar 8 (Uu8) and U. parvum serovar 3 (Up3). ACKR3 responses were assessed via 
      qRT-PCR, RNA sequencing, flow cytometry, and immunocytochemistry. RESULTS: LPS, 
      TNF-alpha, and Ureaplasma spp. influenced ACKR3 expression in HBMEC. LPS and TNF-alpha 
      significantly induced ACKR3 mRNA expression (p < 0.001, vs. control), whereas 
      Ureaplasma spp. enhanced ACKR3 protein expression in HBMEC (p < 0.01, vs. broth 
      control). Co-stimulation with LPS and either Ureaplasma isolate intensified ACKR3 
      responses (p < 0.05, vs. LPS). Furthermore, stimulation wielded a differential 
      influence on the receptor's ligands. CONCLUSIONS: We introduce an in vitro model 
      of Ureaplasma meningitis. We are able to demonstrate a pro-inflammatory capacity 
      of Ureaplasma spp. in native and, even more so, in LPS-primed HBMEC, underlining 
      their clinical relevance particularly in a setting of co-infection. Furthermore, 
      our data may indicate a novel role for ACKR3, with an impact not limited to 
      auto-inflammatory diseases, but extending to infection-related neuroinflammation 
      as well. AKCR3-induced blood-brain barrier breakdown might constitute a potential 
      common pathomechanism.
FAU - Silwedel, Christine
AU  - Silwedel C
AUID- ORCID: 0000-0002-9678-326X
AD  - University Children's Hospital, University of Wuerzburg, Josef-Schneider-Str. 2, 
      97080, Wuerzburg, Germany. Silwedel_C@ukw.de.
FAU - Speer, Christian P
AU  - Speer CP
AD  - University Children's Hospital, University of Wuerzburg, Josef-Schneider-Str. 2, 
      97080, Wuerzburg, Germany.
FAU - Haarmann, Axel
AU  - Haarmann A
AD  - Department of Neurology, University of Wuerzburg, Josef-Schneider-Str. 11, 97080, 
      Wuerzburg, Germany.
FAU - Fehrholz, Markus
AU  - Fehrholz M
AD  - University Children's Hospital, University of Wuerzburg, Josef-Schneider-Str. 2, 
      97080, Wuerzburg, Germany.
FAU - Claus, Heike
AU  - Claus H
AD  - Institute for Hygiene and Microbiology, University of Wuerzburg, 
      Josef-Schneider-Str. 2, 97080, Wuerzburg, Germany.
FAU - Buttmann, Mathias
AU  - Buttmann M
AD  - Department of Neurology, University of Wuerzburg, Josef-Schneider-Str. 11, 97080, 
      Wuerzburg, Germany.
AD  - Department of Neurology, Caritas Hospital, Uhlandstr. 7, 97980, Bad Mergentheim, 
      Germany.
FAU - Glaser, Kirsten
AU  - Glaser K
AD  - University Children's Hospital, University of Wuerzburg, Josef-Schneider-Str. 2, 
      97080, Wuerzburg, Germany.
LA  - eng
PT  - Journal Article
DEP - 20180523
PL  - England
TA  - J Neuroinflammation
JT  - Journal of neuroinflammation
JID - 101222974
RN  - 0 (ACKR3 protein, human)
RN  - 0 (Chemokine CXCL11)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, CXCR)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Brain/cytology
MH  - Cell Line, Transformed
MH  - Chemokine CXCL11/metabolism
MH  - Chemokine CXCL12/metabolism
MH  - Endothelial Cells/*drug effects
MH  - Flow Cytometry
MH  - Humans
MH  - Lipopolysaccharides/*pharmacology
MH  - RNA, Messenger/metabolism
MH  - Receptors, CXCR/genetics/*metabolism
MH  - Time Factors
MH  - Transfection
MH  - Tumor Necrosis Factor-alpha/*pharmacology
MH  - Ureaplasma/*isolation & purification
MH  - Ureaplasma Infections/metabolism/*physiopathology
PMC - PMC5966865
OTO - NOTNLM
OT  - Atypical chemokine receptor 3
OT  - Human brain microvascular endothelial cells
OT  - Meningitis
OT  - Neuroinflammation
OT  - Ureaplasma species
COIS- COMPETING INTERESTS: The authors declare that they have no competing interests. 
      PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional 
      claims in published maps and institutional affiliations.
EDAT- 2018/05/25 06:00
MHDA- 2019/04/09 06:00
PMCR- 2018/05/23
CRDT- 2018/05/25 06:00
PHST- 2018/01/25 00:00 [received]
PHST- 2018/04/19 00:00 [accepted]
PHST- 2018/05/25 06:00 [entrez]
PHST- 2018/05/25 06:00 [pubmed]
PHST- 2019/04/09 06:00 [medline]
PHST- 2018/05/23 00:00 [pmc-release]
AID - 10.1186/s12974-018-1170-0 [pii]
AID - 1170 [pii]
AID - 10.1186/s12974-018-1170-0 [doi]
PST - epublish
SO  - J Neuroinflammation. 2018 May 23;15(1):156. doi: 10.1186/s12974-018-1170-0.