PMID- 36309755
OWN - NLM
STAT- MEDLINE
DCOM- 20221101
LR  - 20221208
IS  - 2051-5960 (Electronic)
IS  - 2051-5960 (Linking)
VI  - 10
IP  - 1
DP  - 2022 Oct 29
TI  - The role of plasminogen activator inhibitor-2 in pneumococcal meningitis.
PG  - 155
LID - 10.1186/s40478-022-01461-1 [doi]
LID - 155
AB  - Pneumococcal meningitis is associated with dysregulation of the coagulation 
      cascade. Previously, we detected upregulation of cerebral plasminogen activator 
      inhibitor-2 (PAI-2) mRNA expression during pneumococcal meningitis. Diverse 
      functions have been ascribed to PAI-2, but its role remains unclear. We analyzed 
      the function of SERPINB2 (coding for PAI-2) in patients with bacterial 
      meningitis, in a well-established pneumococcal meningitis mouse model, using 
      Serpinb2 knockout mice, and in vitro in wt and PAI-2-deficient bone 
      marrow-derived macrophages (BMDMs). We measured PAI-2 in cerebrospinal fluid of 
      patients, and performed functional, histopathological, protein and mRNA 
      expression analyses in vivo and in vitro. We found a substantial increase of 
      PAI-2 concentration in CSF of patients with pneumococcal meningitis, and 
      up-regulation and increased release of PAI-2 in mice. PAI-2 deficiency was 
      associated with increased mortality in murine pneumococcal meningitis and 
      cerebral hemorrhages. Serpinb2(-/-) mice exhibited increased C5a levels, but 
      decreased IL-10 levels in the brain during pneumococcal infection. Our in vitro 
      experiments confirmed increased expression and release of PAI-2 by wt BMDM and 
      decreased IL-10 liberation by PAI-2-deficient BMDM upon pneumococcal challenge. 
      Our data show that PAI-2 is elevated during in pneumococcal meningitis in humans 
      and mice. PAI-2 deficiency causes an inflammatory imbalance, resulting in 
      increased brain pathology and mortality.
CI  - (c) 2022. The Author(s).
FAU - Teske, Nina C
AU  - Teske NC
AD  - Laboratory of Neuroinfectious Diseases, Department of Neurology, Klinikum 
      Grosshadern, Ludwig-Maximilians University, Munich, Germany.
AD  - Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam 
      Neuroscience, PO Box 22660, 1100 DD, Amsterdam, The Netherlands.
AD  - European Society for Clinical Microbiology and Infectious Diseases (ESCMID) Study 
      Group for Infections of the Brain (ESGIB), Basel, Switzerland.
FAU - Engelen-Lee, Joo-Yeon
AU  - Engelen-Lee JY
AD  - Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam 
      Neuroscience, PO Box 22660, 1100 DD, Amsterdam, The Netherlands.
AD  - European Society for Clinical Microbiology and Infectious Diseases (ESCMID) Study 
      Group for Infections of the Brain (ESGIB), Basel, Switzerland.
FAU - Dyckhoff-Shen, Susanne
AU  - Dyckhoff-Shen S
AD  - Laboratory of Neuroinfectious Diseases, Department of Neurology, Klinikum 
      Grosshadern, Ludwig-Maximilians University, Munich, Germany.
FAU - Pfister, Hans-Walter
AU  - Pfister HW
AD  - Laboratory of Neuroinfectious Diseases, Department of Neurology, Klinikum 
      Grosshadern, Ludwig-Maximilians University, Munich, Germany.
FAU - Klein, Matthias
AU  - Klein M
AD  - Laboratory of Neuroinfectious Diseases, Department of Neurology, Klinikum 
      Grosshadern, Ludwig-Maximilians University, Munich, Germany.
AD  - European Society for Clinical Microbiology and Infectious Diseases (ESCMID) Study 
      Group for Infections of the Brain (ESGIB), Basel, Switzerland.
FAU - van de Beek, Diederik
AU  - van de Beek D
AD  - Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam 
      Neuroscience, PO Box 22660, 1100 DD, Amsterdam, The Netherlands.
AD  - European Society for Clinical Microbiology and Infectious Diseases (ESCMID) Study 
      Group for Infections of the Brain (ESGIB), Basel, Switzerland.
FAU - Kirschning, Carsten K
AU  - Kirschning CK
AD  - Institute of Medical Microbiology, University of Duisburg-Essen, Essen, Germany.
FAU - Koedel, Uwe
AU  - Koedel U
AD  - Laboratory of Neuroinfectious Diseases, Department of Neurology, Klinikum 
      Grosshadern, Ludwig-Maximilians University, Munich, Germany.
AD  - European Society for Clinical Microbiology and Infectious Diseases (ESCMID) Study 
      Group for Infections of the Brain (ESGIB), Basel, Switzerland.
FAU - Brouwer, Matthijs C
AU  - Brouwer MC
AUID- ORCID: 0000-0001-7775-7843
AD  - Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam 
      Neuroscience, PO Box 22660, 1100 DD, Amsterdam, The Netherlands. 
      m.c.brouwer@amsterdamumc.nl.
AD  - European Society for Clinical Microbiology and Infectious Diseases (ESCMID) Study 
      Group for Infections of the Brain (ESGIB), Basel, Switzerland. 
      m.c.brouwer@amsterdamumc.nl.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221029
PL  - England
TA  - Acta Neuropathol Commun
JT  - Acta neuropathologica communications
JID - 101610673
RN  - 0 (Plasminogen Activator Inhibitor 2)
RN  - 130068-27-8 (Interleukin-10)
RN  - 0 (RNA, Messenger)
SB  - IM
MH  - Humans
MH  - Mice
MH  - Animals
MH  - *Meningitis, Pneumococcal/genetics
MH  - Plasminogen Activator Inhibitor 2/genetics
MH  - Interleukin-10
MH  - Mice, Knockout
MH  - RNA, Messenger
MH  - Mice, Inbred C57BL
PMC - PMC9617400
OTO - NOTNLM
OT  - Plasminogen activator inhibitor-2
OT  - Pneumococcal meningitis
OT  - SERPINB2
COIS- The authors declare that they have no competing interests.
EDAT- 2022/10/31 06:00
MHDA- 2022/11/02 06:00
PMCR- 2022/10/29
CRDT- 2022/10/30 01:12
PHST- 2022/09/07 00:00 [received]
PHST- 2022/10/12 00:00 [accepted]
PHST- 2022/10/30 01:12 [entrez]
PHST- 2022/10/31 06:00 [pubmed]
PHST- 2022/11/02 06:00 [medline]
PHST- 2022/10/29 00:00 [pmc-release]
AID - 10.1186/s40478-022-01461-1 [pii]
AID - 1461 [pii]
AID - 10.1186/s40478-022-01461-1 [doi]
PST - epublish
SO  - Acta Neuropathol Commun. 2022 Oct 29;10(1):155. doi: 10.1186/s40478-022-01461-1.