Key Points

  • Lethality of TM-null embryos is not a consequence of placental NLRP3 inflammasome activation.

  • EV-induced and platelet-mediated inflammasome activation reduces placental TM expression and proliferation, aiding fetal demise in PE.

Abstract

Excess platelet activation by extracellular vesicles (EVs) results in trophoblast inflammasome activation, interleukin 1β (IL-1β) activation, preeclampsia (PE), and partial embryonic lethality. Embryonic thrombomodulin (TM) deficiency, which causes embryonic lethality hallmarked by impaired trophoblast proliferation, has been linked with maternal platelet activation. We hypothesized that placental TM loss, platelet activation, and embryonic lethality are mechanistically linked to trophoblast inflammasome activation. Here, we uncover unidirectional interaction of placental inflammasome activation and reduced placental TM expression: although inflammasome inhibition did not rescue TM-null embryos from lethality, the inflammasome-dependent cytokine IL-1β reduced trophoblast TM expression and impaired pregnancy outcome. EVs, known to induce placental inflammasome activation, reduced trophoblast TM expression and proliferation. Trophoblast TM expression correlated negatively with IL-1β expression and positively with platelet numbers and trophoblast proliferation in human PE placentae, implying translational relevance. Soluble TM treatment or placental TM restoration ameliorated the EV-induced PE-like phenotype in mice, preventing placental thromboinflammation and embryonic death. The lethality of TM-null embryos is not a consequence of placental NLRP3 inflammasome activation. Conversely, EV-induced placental inflammasome activation reduces placental TM expression, promoting placental and embryonic demise. These data identify a new function of placental TM in PE and suggest that soluble TM limits thromboinflammatory pregnancy complications.

REFERENCES

REFERENCES
1.
MacKay
AP
,
Berg
CJ
,
Atrash
HK
.
Pregnancy-related mortality from preeclampsia and eclampsia
.
Obstet Gynecol
.
2001
;
97
(
4
):
533
-
538
.
2.
Lockwood
CJ
.
Pregnancy-associated changes in the hemostatic system
.
Clin Obstet Gynecol
.
2006
;
49
(
4
):
836
-
843
.
3.
Sood
R
,
Kalloway
S
,
Mast
AE
,
Hillard
CJ
,
Weiler
H
.
Fetomaternal cross talk in the placental vascular bed: control of coagulation by trophoblast cells
.
Blood
.
2006
;
107
(
8
):
3173
-
3180
.
4.
Kohli
S
,
Isermann
B
.
Placental hemostasis and sterile inflammation: new insights into gestational vascular disease
.
Thromb Res
.
2017
;
151
(
suppl 1
):
S30
-
S33
.
5.
Isermann
B
,
Hendrickson
SB
,
Hutley
K
,
Wing
M
,
Weiler
H
.
Tissue-restricted expression of thrombomodulin in the placenta rescues thrombomodulin-deficient mice from early lethality and reveals a secondary developmental block
.
Development
.
2001
;
128
(
6
):
827
-
838
.
6.
Kohli
S
,
Hoffmann
J
,
Lochmann
F
, et al
.
p45 NF-E2 regulates syncytiotrophoblast differentiation by post-translational GCM1 modifications in human intrauterine growth restriction
.
Cell Death Dis
.
2017
;
8
(
4
):
e2730
.
7.
Healy
AM
,
Rayburn
HB
,
Rosenberg
RD
,
Weiler
H
.
Absence of the blood-clotting regulator thrombomodulin causes embryonic lethality in mice before development of a functional cardiovascular system
.
Proc Natl Acad Sci USA
.
1995
;
92
(
3
):
850
-
854
.
8.
Isermann
B
,
Sood
R
,
Pawlinski
R
, et al
.
The thrombomodulin-protein C system is essential for the maintenance of pregnancy
.
Nat Med
.
2003
;
9
(
3
):
331
-
337
.
9.
Sood
R
,
Sholl
L
,
Isermann
B
,
Zogg
M
,
Coughlin
SR
,
Weiler
H
.
Maternal Par4 and platelets contribute to defective placenta formation in mouse embryos lacking thrombomodulin
.
Blood
.
2008
;
112
(
3
):
585
-
591
.
10.
Kohli
S
,
Ranjan
S
,
Hoffmann
J
, et al
.
Maternal extracellular vesicles and platelets promote preeclampsia via inflammasome activation in trophoblasts
.
Blood
.
2016
;
128
(
17
):
2153
-
2164
.
11.
Turner
RJ
,
Bloemenkamp
KW
,
Bruijn
JA
,
Baelde
HJ
.
Loss of thrombomodulin in placental dysfunction in preeclampsia
.
Arterioscler Thromb Vasc Biol
.
2016
;
36
(
4
):
728
-
735
.
12.
Schwenk
F
,
Baron
U
,
Rajewsky
K
.
A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells
.
Nucleic Acids Res
.
1995
;
23
(
24
):
5080
-
5081
.
13.
Wolter
J
,
Schild
L
,
Bock
F
, et al
.
Thrombomodulin-dependent protein C activation is required for mitochondrial function and myelination in the central nervous system
.
J Thromb Haemost
.
2016
;
14
(
11
):
2212
-
2226
.
14.
van Iersel
T
,
Stroissnig
H
,
Giesen
P
,
Wemer
J
,
Wilhelm-Ogunbiyi
K
.
Phase I study of solulin, a novel recombinant soluble human thrombomodulin analogue
.
Thromb Haemost
.
2011
;
105
(
2
):
302
-
312
.
15.
Sood
R
,
Zogg
M
,
Westrick
RJ
, et al
.
Fetal gene defects precipitate platelet-mediated pregnancy failure in factor V Leiden mothers
.
J Exp Med
.
2007
;
204
(
5
):
1049
-
1056
.
16.
Rolnik
DL
,
Wright
D
,
Poon
LC
, et al
.
Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia
.
N Engl J Med
.
2017
;
377
(
7
):
613
-
622
.
17.
Shin
M
,
Hino
H
,
Tamura
M
, et al
.
Thrombomodulin improves maternal and fetal conditions in an experimental pre-eclampsia rat model
.
J Obstet Gynaecol Res
.
2014
;
40
(
5
):
1226
-
1234
.
18.
Sano
T
,
Terai
Y
,
Daimon
A
, et al
.
Recombinant human soluble thrombomodulin as an anticoagulation therapy improves recurrent miscarriage and fetal growth restriction due to placental insufficiency - the leading cause of preeclampsia
.
Placenta
.
2018
;
65
:
1
-
6
.
You do not currently have access to this content.

Sign in via your Institution

Sign In