PMID- 35158413
OWN - NLM
STAT- MEDLINE
DCOM- 20220422
LR  - 20231219
IS  - 1538-7836 (Electronic)
IS  - 1538-7933 (Print)
IS  - 1538-7836 (Linking)
VI  - 20
IP  - 5
DP  - 2022 May
TI  - Cross-linking by tissue transglutaminase-2 alters fibrinogen-directed macrophage 
      proinflammatory activity.
PG  - 1182-1192
LID - 10.1111/jth.15670 [doi]
AB  - BACKGROUND: The blood coagulation factor fibrin(ogen) can modulate inflammation 
      by altering leukocyte activity. Analyses of fibrin(ogen)-mediated proinflammatory 
      activity have largely focused on leukocyte integrin binding activity revealed by 
      conversion of fibrinogen to a stabilized fibrin polymer by blood coagulation 
      enzymes. In addition to coagulation enzymes, fibrinogen is a substrate for tissue 
      transglutaminase-2 (TG2), a widely expressed enzyme that produces unique 
      fibrinogen Aalpha-gamma chain cross-linked products. OBJECTIVES: We tested the hypothesis 
      that TG2 dependent cross-linking alters the proinflammatory activity of 
      surface-adhered fibrinogen. METHODS: Mouse bone marrow-derived macrophages 
      (BMDMs) were cultured on tissue culture plates coated with fibrinogen or 
      TG2-cross-linked fibrinogen (10 microg/ml) and then stimulated with 
      lipopolysaccharide (LPS, 1 ng/ml) or vehicle for various times. RESULTS: In the 
      absence of LPS stimulation, TG2-cross-linked fibrin(ogen) enhanced inflammatory 
      gene induction (e.g., Tnfalpha) compared with unmodified fibrinogen. LPS stimulation 
      induced mitogen-activated protein kinase phosphorylation, IkappaBalpha degradation, and 
      expression of proinflammatory cytokines (e.g., tumor necrosis factor alpha) within 
      60 min. This initial cellular activation was unaffected by unmodified or 
      TG2-cross-linked fibrinogen. In contrast, LPS induction of interleukin-10 mRNA 
      and protein and STAT3 phosphorylation was selectively attenuated by 
      TG2-cross-linked fibrinogen, which was associated with enhanced proinflammatory 
      cytokine secretion by LPS-stimulated BMDMs at later time points (6 and 24 h). 
      CONCLUSIONS: The results indicate that atypical cross-linking by TG2 imparts 
      unique proinflammatory activity to surface-adhered fibrinogen. The results 
      suggest a novel coagulation-independent mechanism controlling fibrinogen-directed 
      macrophage activation.
CI  - (c) 2022 International Society on Thrombosis and Haemostasis.
FAU - Poole, Lauren G
AU  - Poole LG
AUID- ORCID: 0000-0002-5405-5774
AD  - Department of Pathobiology & Diagnostic Investigation, Michigan State University, 
      East Lansing, Michigan, USA.
AD  - Institute for Integrative Toxicology, Michigan State University, East Lansing, 
      Michigan, USA.
FAU - Kopec, Anna K
AU  - Kopec AK
AD  - Department of Pathobiology & Diagnostic Investigation, Michigan State University, 
      East Lansing, Michigan, USA.
AD  - Institute for Integrative Toxicology, Michigan State University, East Lansing, 
      Michigan, USA.
FAU - Flick, Matthew J
AU  - Flick MJ
AD  - Department of Pathology and Laboratory Medicine, UNC Blood Research Center, 
      Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, North Carolina, USA.
FAU - Luyendyk, James P
AU  - Luyendyk JP
AUID- ORCID: 0000-0003-3174-8583
AD  - Department of Pathobiology & Diagnostic Investigation, Michigan State University, 
      East Lansing, Michigan, USA.
AD  - Institute for Integrative Toxicology, Michigan State University, East Lansing, 
      Michigan, USA.
AD  - Department of Pharmacology and Toxicology, Michigan State University, East 
      Lansing, Michigan, USA.
LA  - eng
GR  - R01 DK120289/DK/NIDDK NIH HHS/United States
GR  - F32 DK121423/DK/NIDDK NIH HHS/United States
GR  - K99 DK129710/DK/NIDDK NIH HHS/United States
GR  - R01 ES017537/ES/NIEHS NIH HHS/United States
GR  - R01 DK112778/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20220227
PL  - England
TA  - J Thromb Haemost
JT  - Journal of thrombosis and haemostasis : JTH
JID - 101170508
RN  - 0 (Lipopolysaccharides)
RN  - 0 (TG2 protein, mouse)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 9001-31-4 (Fibrin)
RN  - 9001-32-5 (Fibrinogen)
RN  - EC 2.3.2.13 (Protein Glutamine gamma Glutamyltransferase 2)
RN  - EC 2.3.2.13 (Transglutaminases)
SB  - IM
MH  - Animals
MH  - Fibrin/metabolism
MH  - Fibrinogen/metabolism
MH  - Humans
MH  - *Lipopolysaccharides
MH  - Macrophages/metabolism
MH  - Mice
MH  - *Protein Glutamine gamma Glutamyltransferase 2
MH  - Transglutaminases/genetics/metabolism
MH  - Tumor Necrosis Factor-alpha
PMC - PMC9035112
MID - NIHMS1781715
OTO - NOTNLM
OT  - fibrinogen
OT  - inflammation
OT  - lipopolysaccharide
OT  - macrophage
OT  - transglutaminase
COIS- Conflicts of Interest: L.G. Poole, A. K. Kopec, M. J. Flick, and J.P. Luyendyk 
      express no conflicts of interest regarding this work.
EDAT- 2022/02/15 06:00
MHDA- 2022/04/23 06:00
PMCR- 2023/05/01
CRDT- 2022/02/14 20:18
PHST- 2022/01/21 00:00 [revised]
PHST- 2021/09/27 00:00 [received]
PHST- 2022/02/07 00:00 [accepted]
PHST- 2022/02/15 06:00 [pubmed]
PHST- 2022/04/23 06:00 [medline]
PHST- 2022/02/14 20:18 [entrez]
PHST- 2023/05/01 00:00 [pmc-release]
AID - S1538-7836(22)00162-3 [pii]
AID - 10.1111/jth.15670 [doi]
PST - ppublish
SO  - J Thromb Haemost. 2022 May;20(5):1182-1192. doi: 10.1111/jth.15670. Epub 2022 Feb 
      27.