PMID- 31416821
OWN - NLM
STAT- MEDLINE
DCOM- 20200817
LR  - 20200817
IS  - 2473-9537 (Electronic)
IS  - 2473-9529 (Print)
IS  - 2473-9529 (Linking)
VI  - 3
IP  - 16
DP  - 2019 Aug 27
TI  - Monocyte procoagulant responses to anthrax peptidoglycan are reinforced by 
      proinflammatory cytokine signaling.
PG  - 2436-2447
LID - 10.1182/bloodadvances.2019000513 [doi]
AB  - Disseminated intravascular coagulation is a frequent manifestation during 
      bacterial infections and is associated with negative clinical outcomes. 
      Imbalanced expression and activity of intravascular tissue factor (TF) is central 
      to the development of infection-associated coagulopathies. Recently, we showed 
      that anthrax peptidoglycan (PGN) induces disseminated intravascular coagulation 
      in a nonhuman primate model of anthrax sepsis. We hypothesized that immune 
      recognition of PGN by monocytes is critical for procoagulant responses to PGN and 
      investigated whether and how PGN induces TF expression in primary human 
      monocytes. We found that PGN induced monocyte TF expression in a large cohort of 
      healthy volunteers similar to lipopolysaccharide stimulation. Both immune and 
      procoagulant responses to PGN involve intracellular recognition after PGN 
      internalization, as well as surface signaling through immune Fcgamma receptors 
      (FcgammaRs). In line with our hypothesis, blocking immune receptor function, both 
      signaling and FcgammaR-mediated phagocytosis, significantly reduced but did not 
      abolish PGN-induced monocyte TF expression, indicating that FcgammaR-independent 
      internalization contributes to intracellular recognition of PGN. Conversely, when 
      intracellular PGN recognition is abolished, TF expression was sensitive to 
      inhibitors of FcgammaR signaling, indicating that surface engagement of monocyte 
      immune receptors can promote TF expression. The primary procoagulant responses to 
      PGN were further amplified by proinflammatory cytokines through paracrine and 
      autocrine signaling. Despite intersubject variability in the study cohort, dual 
      neutralization of tumor necrosis factor-alpha and interleukin-1beta provided the most 
      robust inhibition of the procoagulant amplification loop and may prove useful for 
      reducing coagulopathies in gram-positive sepsis.
CI  - (c) 2019 by The American Society of Hematology.
FAU - Popescu, Narcis Ioan
AU  - Popescu NI
AUID- ORCID: 0000-0002-4809-9885
AD  - Department of Arthritis and Clinical Immunology, Oklahoma Medical Research 
      Foundation, Oklahoma City, OK.
FAU - Girton, Alanson
AU  - Girton A
AUID- ORCID: 0000-0001-8101-8269
AD  - Department of Arthritis and Clinical Immunology, Oklahoma Medical Research 
      Foundation, Oklahoma City, OK.
FAU - Burgett, Tarea
AU  - Burgett T
AD  - Department of Arthritis and Clinical Immunology, Oklahoma Medical Research 
      Foundation, Oklahoma City, OK.
FAU - Lovelady, Kessa
AU  - Lovelady K
AD  - Department of Arthritis and Clinical Immunology, Oklahoma Medical Research 
      Foundation, Oklahoma City, OK.
FAU - Coggeshall, K Mark
AU  - Coggeshall KM
AUID- ORCID: 0000-0003-4797-9095
AD  - Department of Arthritis and Clinical Immunology, Oklahoma Medical Research 
      Foundation, Oklahoma City, OK.
LA  - eng
GR  - R21 AI113020/AI/NIAID NIH HHS/United States
GR  - U19 AI062629/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Blood Adv
JT  - Blood advances
JID - 101698425
RN  - 0 (Biomarkers)
RN  - 0 (Cytokines)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Peptidoglycan)
RN  - 20350-15-6 (Brefeldin A)
RN  - 9035-58-9 (Thromboplastin)
SB  - IM
MH  - Anthrax/*immunology
MH  - Biomarkers
MH  - Blood Coagulation/drug effects/*immunology
MH  - Brefeldin A/pharmacology
MH  - Cytokines/*metabolism
MH  - Flow Cytometry
MH  - Host-Pathogen Interactions/immunology
MH  - Humans
MH  - Inflammation Mediators/*metabolism
MH  - Leukocytes, Mononuclear/immunology/metabolism
MH  - Lipopolysaccharides/immunology
MH  - Monocytes/drug effects/*immunology/*metabolism
MH  - Peptidoglycan/*immunology
MH  - *Signal Transduction/drug effects
MH  - Thromboplastin/metabolism
PMC - PMC6712522
COIS- Conflict-of-interest disclosure: The authors declare no competing financial 
      interests.
EDAT- 2019/08/17 06:00
MHDA- 2020/08/18 06:00
PMCR- 2019/08/15
CRDT- 2019/08/17 06:00
PHST- 2019/02/05 00:00 [received]
PHST- 2019/06/17 00:00 [accepted]
PHST- 2019/08/17 06:00 [entrez]
PHST- 2019/08/17 06:00 [pubmed]
PHST- 2020/08/18 06:00 [medline]
PHST- 2019/08/15 00:00 [pmc-release]
AID - bloodadvances.2019000513 [pii]
AID - 2019/ADV2019000513 [pii]
AID - 10.1182/bloodadvances.2019000513 [doi]
PST - ppublish
SO  - Blood Adv. 2019 Aug 27;3(16):2436-2447. doi: 10.1182/bloodadvances.2019000513.