Monocytes Expose Factor XIII-A and Stabilize Thrombi against Fibrinolytic Degradation

Factor XIII (FXIII) is a transglutaminase that promotes thrombus stability by cross-linking fibrin. The cellular form, a homodimer of the A subunits, denoted FXIII-A, lacks a classical signal peptide for its release; however, we have shown that it is exposed on activated platelets. Here we addressed...

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Bibliographic Details
Published in:International journal of molecular sciences 2021-06, Vol.22 (12), p.6591
Main Authors: Alshehri, Fahad S M, Whyte, Claire S, Tuncay, Ahmet, Williams, Maria-Louise, Wilson, Heather M, Mutch, Nicola J
Format: Article
Language:English
Subjects:
Antigens
Blood clots
Coagulation factors
Crosslinking
Cytoplasm
Exposure
Factor XIIIa - metabolism
Fibrin
Flow cytometry
Fractionation
Healthy Volunteers
Humans
Interleukin 10
Interleukin 4
Lipopolysaccharides
Lysates
Membranes
Microscopy
Monocytes
Monocytes - metabolism
Plasma
Stimulation
THP-1 Cells - metabolism
Thrombosis
Thrombosis - metabolism
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Summary:Factor XIII (FXIII) is a transglutaminase that promotes thrombus stability by cross-linking fibrin. The cellular form, a homodimer of the A subunits, denoted FXIII-A, lacks a classical signal peptide for its release; however, we have shown that it is exposed on activated platelets. Here we addressed whether monocytes expose intracellular FXIII-A in response to stimuli. Using flow cytometry, we demonstrate that FXIII-A antigen and activity are up-regulated on human monocytes in response to stimulation by IL-4 and IL-10. Higher basal levels of the FXIII-A antigen were noted on the membrane of the monocytic cell line THP-1, but activity was significantly enhanced following stimulation with IL-4 and IL-10. In contrast, treatment with lipopolysaccharide did not upregulate exposure of FXIII-A in THP-1 cells. Quantification of the FXIII-A activity revealed a significant increase in THP-1 cells in total cell lysates following stimulation with IL-4 and IL-10. Following fractionation, the largest pool of FXIII-A was membrane associated. Monocytes were actively incorporated into the fibrin mesh of model thrombi. We found that stimulation of monocytes and THP-1 cells with IL-4 and IL-10 stabilized FXIII-depleted thrombi against fibrinolytic degradation, via a transglutaminase-dependent mechanism. Our data suggest that monocyte-derived FXIII-A externalized in response to stimuli participates in thrombus stabilization.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms22126591