TY - JOUR
T1 - Factor XI deficiency alters the cytokine response and activation of contact proteases during polymicrobial sepsis in mice
AU - Bane, Charles E.
AU - Ivanov, Ivan
AU - Matafonov, Anton
AU - Boyd, Kelli L.
AU - Cheng, Qiufang
AU - Sherwood, Edward R.
AU - Tucker, Erik I.
AU - Smiley, Stephen T.
AU - McCarty, Owen J.T.
AU - Gruber, Andras
AU - Gailani, David
N1 - Funding Information:
DG is a consultant, and receives consultant’s fees from the following companies with an interest in the role of factor XI in thrombosis: Bayer Pharma, Dyax Corp., Novartis, Isis Pharmaceuticals and Ono Pharma. None of these corporations provided support for the work presented in this manuscript. In addition. DG is on the scientific advisory board of Aronora, which also has an interest in the role of factor XI in thrombosis. Aronora did not provide financial support for the work in described in this manuscript. EIT and AG are employees of the company Aronora, and receive salary support from that entity. Other than salary support, Aronora did not provide financial support for the work in described in this manuscript. These investigators have collaborated with DG and his colleagues on projects funded by the NIH grants supporting the work on sepsis. None of the arrangements described in this sections not alters the authors' adherence to PLOS ONE policies on sharing data and materials as detailed in the guide for authors ( http://www.PLOSone.org/static/editorial.action#competing ).
PY - 2016/4
Y1 - 2016/4
N2 - Sepsis, a systemic inflammatory response to infection, is often accompanied by abnormalities of blood coagulation. Prior work with a mouse model of sepsis induced by cecal ligation and puncture (CLP) suggested that the protease factor XIa contributed to disseminated intravascular coagulation (DIC) and to the cytokine response during sepsis. We investigated the importance of factor XI to cytokine and coagulation responses during the first 24 hours after CLP. Compared to wild type littermates, factor XI-deficient (FXI-/-) mice had a survival advantage after CLP, with smaller increases in plasma levels of TNF-α and IL-10 and delayed IL-1β and IL-6 responses. Plasma levels of serum amyloid P, an acute phase protein, were increased in wild type mice 24 hours post-CLP, but not in FXI-/- mice, supporting the impression of a reduced inflammatory response in the absence of factor XI. Surprisingly, there was little evidence of DIC in mice of either genotype. Plasma levels of the contact factors factor XII and prekallikrein were reduced in WT mice after CLP, consistent with induction of contact activation. However, factor XII and PK levels were not reduced in FXI-/- animals, indicating factor XI deficiency blunted contact activation. Intravenous infusion of polyphosphate into WT mice also induced changes in factor XII, but had much less effect in FXI deficient mice. In vitro analysis revealed that factor XIa activates factor XII, and that this reaction is enhanced by polyanions such polyphosphate and nucleic acids. These data suggest that factor XI deficiency confers a survival advantage in the CLP sepsis model by altering the cytokine response to infection and blunting activation of the contact (kallikrein-kinin) system. The findings support the hypothesis that factor XI functions as a bidirectional interface between contact activation and thrombin generation, allowing the two processes to influence each other.
AB - Sepsis, a systemic inflammatory response to infection, is often accompanied by abnormalities of blood coagulation. Prior work with a mouse model of sepsis induced by cecal ligation and puncture (CLP) suggested that the protease factor XIa contributed to disseminated intravascular coagulation (DIC) and to the cytokine response during sepsis. We investigated the importance of factor XI to cytokine and coagulation responses during the first 24 hours after CLP. Compared to wild type littermates, factor XI-deficient (FXI-/-) mice had a survival advantage after CLP, with smaller increases in plasma levels of TNF-α and IL-10 and delayed IL-1β and IL-6 responses. Plasma levels of serum amyloid P, an acute phase protein, were increased in wild type mice 24 hours post-CLP, but not in FXI-/- mice, supporting the impression of a reduced inflammatory response in the absence of factor XI. Surprisingly, there was little evidence of DIC in mice of either genotype. Plasma levels of the contact factors factor XII and prekallikrein were reduced in WT mice after CLP, consistent with induction of contact activation. However, factor XII and PK levels were not reduced in FXI-/- animals, indicating factor XI deficiency blunted contact activation. Intravenous infusion of polyphosphate into WT mice also induced changes in factor XII, but had much less effect in FXI deficient mice. In vitro analysis revealed that factor XIa activates factor XII, and that this reaction is enhanced by polyanions such polyphosphate and nucleic acids. These data suggest that factor XI deficiency confers a survival advantage in the CLP sepsis model by altering the cytokine response to infection and blunting activation of the contact (kallikrein-kinin) system. The findings support the hypothesis that factor XI functions as a bidirectional interface between contact activation and thrombin generation, allowing the two processes to influence each other.
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U2 - 10.1371/journal.pone.0152968
DO - 10.1371/journal.pone.0152968
M3 - Article
C2 - 27046148
AN - SCOPUS:84962917515
SN - 1932-6203
VL - 11
JO - PLoS One
JF - PLoS One
IS - 4
M1 - e0152968
ER -