Histones induce rapid and profound thrombocytopenia in mice
Standard
Histones induce rapid and profound thrombocytopenia in mice. / Fuchs, Tobias A; Bhandari, Ashish A; Wagner, Denisa D.
In: BLOOD, Vol. 118, No. 13, 29.09.2011, p. 3708-14.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Histones induce rapid and profound thrombocytopenia in mice
AU - Fuchs, Tobias A
AU - Bhandari, Ashish A
AU - Wagner, Denisa D
PY - 2011/9/29
Y1 - 2011/9/29
N2 - Histones are released from dying cells and contribute to antimicrobial defense during infection. However, extracellular histones are a double-edged sword because they also damage host tissue and may cause death. We studied the interactions of histones with platelets. Histones bound to platelets, induced calcium influx, and recruited plasma adhesion proteins such as fibrinogen to induce platelet aggregation. Hereby fibrinogen cross-linked histone-bearing platelets and triggered microaggregation. Fibrinogen interactions with αIIbβ3 integrins were not required for this process but were necessary for the formation of large platelet aggregates. Infused histones associated with platelets in vivo and caused a profound thrombocytopenia within minutes after administration. Mice lacking platelets or αIIbβ3 integrins were protected from histone-induced death but not from histone-induced tissue damage. Heparin, at high concentrations, prevented histone interactions with platelets and protected mice from histone-induced thrombocytopenia, tissue damage, and death. Heparin and histones are evolutionary maintained. Histones may combine microbicidal with prothrombotic properties to fight invading microbes and maintain hemostasis after injury. Heparin may provide an innate counter mechanism to neutralize histones and diminish collateral tissue damage.
AB - Histones are released from dying cells and contribute to antimicrobial defense during infection. However, extracellular histones are a double-edged sword because they also damage host tissue and may cause death. We studied the interactions of histones with platelets. Histones bound to platelets, induced calcium influx, and recruited plasma adhesion proteins such as fibrinogen to induce platelet aggregation. Hereby fibrinogen cross-linked histone-bearing platelets and triggered microaggregation. Fibrinogen interactions with αIIbβ3 integrins were not required for this process but were necessary for the formation of large platelet aggregates. Infused histones associated with platelets in vivo and caused a profound thrombocytopenia within minutes after administration. Mice lacking platelets or αIIbβ3 integrins were protected from histone-induced death but not from histone-induced tissue damage. Heparin, at high concentrations, prevented histone interactions with platelets and protected mice from histone-induced thrombocytopenia, tissue damage, and death. Heparin and histones are evolutionary maintained. Histones may combine microbicidal with prothrombotic properties to fight invading microbes and maintain hemostasis after injury. Heparin may provide an innate counter mechanism to neutralize histones and diminish collateral tissue damage.
KW - Animals
KW - Disease Models, Animal
KW - Fibrinogen
KW - Histones
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Platelet Aggregation
KW - Platelet Glycoprotein GPIIb-IIIa Complex
KW - Severity of Illness Index
KW - Thrombocytopenia
KW - Time Factors
KW - Up-Regulation
U2 - 10.1182/blood-2011-01-332676
DO - 10.1182/blood-2011-01-332676
M3 - SCORING: Journal article
C2 - 21700775
VL - 118
SP - 3708
EP - 3714
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 13
ER -