Antiplatelet Activities of Anthrax Lethal Toxin Are Associated with Suppressed p42/44 and p38 Mitogen‐Activated Protein Kinase Pathways in the Platelets

Kau, Jyh-Hwa; Sun, Der-Shan; Tsai, Wei‐Jern; Shyu, Huey-Fen; Huang, Hsin-Hsien; Lin, Herng Ching; Chang, Hsin-Hou

doi:10.1086/491477

Cited by 46 publications

(62 citation statements)

References 54 publications

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“…17 Our previous study demonstrated an inhibitory role of LT on platelet activation. 14 In the present study, we further found that LT challenges suppressed and prolonged the plasma clotting of mice. In this experiment, platelet-poor plasma was affected, suggesting that LT suppresses not only platelets but also coagulant factors of the plasma.…”

Section: Introductionsupporting

confidence: 73%

“…11,44,45 In animal models, hemorrhage was observed in mediastinal, mesenteric, and tracheobronchial lymph nodes, as well as in the meninges, lungs, and small intestinal serosas of B. anthracis-infected animals. 11 Because LT treatments induce hemorrhage, 14,46 these results might indicate that anthrax LT is involved in the hemorrhagic pathogenesis. Previously, we determined that LT suppresses platelet functions 14 ; however, the influence of LT treatments on coagulant factors remained unclear.…”

Section: Discussionmentioning

confidence: 99%

“…11 Because LT treatments induce hemorrhage, 14,46 these results might indicate that anthrax LT is involved in the hemorrhagic pathogenesis. Previously, we determined that LT suppresses platelet functions 14 ; however, the influence of LT treatments on coagulant factors remained unclear. In the present study, we found that the expression of FVIII in mouse livers was suppressed using LT treatments at a disease stage before to the occurrence of mortality.…”

Section: Discussionmentioning

confidence: 99%

“…For example, among 3 MAPK pathways, only p38 MAPK is involved in LT-induced macrophage apoptosis, 33 whereas both p42/44 and p38 MAPKs are associated with LT-mediated suppression on platelets. 14 Consequently, we applied a pharmacological approach to investigate which MAPK pathway is involved in the suppression of hepatic cells. The selective inhibitors U0126 (MEK1/2 inhibitor; MEK1/2 are upstream regulators of p42/44 MAPK), SB202190 (p38 inhibitor) and SP600125 (JNK inhibitor), all of which have been compared with LT in inhibiting MAPKs, 34,35 were employed.…”

Section: Lt Treatments Prolong Plasma Clottingmentioning

confidence: 99%

“…[7][8][9][10][11][12][13] Recent studies have shown that LT might contribute to hemorrhage by inducing thrombocytopenia and megakaryocytic suppression. [14][15][16] The mechanism underlying coagulation suppression, however, remains undetermined.…”

Section: Introductionmentioning

confidence: 99%

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Acquired coagulant factor VIII deficiency induced byBacillus anthracislethal toxin in mice

Sun¹,

Lee

Kau

et al. 2015

Virulence

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(2015) Acquired coagulant factor VIII deficiency induced by Bacillus anthracis lethal toxin in mice, Virulence, 6:5, 466-475, DOI: 10.1080/21505594.2015 Keywords: Anthrax, coagulation factor VIII, hemorrhage, lethal toxinMice treated with anthrax lethal toxin (LT) exhibit hemorrhage caused by unknown mechanisms. Moreover, LT treatment in mice induced liver damage. In this study, we hypothesized that a suppressed coagulation function may be associated with liver damage, because the liver is the major producing source of coagulation factors. The hepatic expression of coagulant factors and the survival rates were analyzed after cultured cells or mice were exposed to LT. In agreement with our hypothesis, LT induces cytotoxicity against hepatic cells in vitro. In addition, suppressed expression of coagulation factor VIII (FVIII) in the liver is associated with a prolonged plasma clotting time in LT-treated mice, suggesting a suppressive role of LT in coagulation. Accordingly, we further hypothesized that a loss-of-function approach involving treatments of an anticoagulant should exacerbate LT-induced abnormalities, whereas a gain-offunction approach involving injections of recombinant FVIII to complement the coagulation deficiency should ameliorate the pathogenesis. As expected, a sublethal dose of LT caused mortality in the mice that were non-lethally pretreated with an anticoagulant (warfarin). By contrast, treatments of recombinant FVIII reduced the mortality from a lethal dose of LT in mice. Our results indicated that LT-induced deficiency of FVIII is involved in LT-mediated pathogenesis. Using recombinant FVIII to correct the coagulant defect may enable developing a new strategy to treat anthrax.

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Section: Introductionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Lt Treatments Prolong Plasma Clottingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acquired coagulant factor VIII deficiency induced byBacillus anthracislethal toxin in mice

Sun¹,

Lee

Kau

et al. 2015

Virulence

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Anthrax Toxins

Moayeri

Leppla

2010

Bacillus Anthracis and Anthrax

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Frontline Science: Anthrax lethal toxin-induced, NLRP1-mediated IL-1β release is a neutrophil and PAD4-dependent event

Greaney

Portley

O’Mard

et al. 2020

Journal of Leukocyte Biology

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Anthrax lethal toxin (LT) is a protease that activates the NLRP1b inflammasome sensor in certain rodent strains. Unlike better‐studied sensors, relatively little is known about the priming requirements for NLRP1b. In this study, we investigate the rapid and striking priming‐independent LT‐induced release of IL‐1β in mice within hours of toxin challenge. We find IL‐1β release to be a NLRP1b‐ and caspase‐1‐dependent, NLRP3 and caspase‐11‐independent event that requires both neutrophils and peptidyl arginine deiminiase‐4 (PAD4) activity. The simultaneous LT‐induced IL‐18 response is neutrophil‐independent. Bone marrow reconstitution experiments in mice show toxin‐induced IL‐1β originates from hematopoietic cells. LT treatment of neutrophils in vitro did not induce IL‐1β, neutrophil extracellular traps (NETs), or pyroptosis. Although platelets interact closely with neutrophils and are also a potential source of IL‐1β, they were unable to bind or endocytose LT and did not secrete IL‐1β in response to the toxin. LT‐treated mice had higher levels of cell‐free DNA and HMGB1 in circulation than PBS‐treated controls, and treatment of mice with recombinant DNase reduced the neutrophil‐ and NLRP1‐dependent IL‐1β release. DNA sensor AIM2 deficiency, however, did not impact IL‐1β release. These data, in combination with the findings on PAD4, suggest a possible role for in vivo NETs or cell‐free DNA in cytokine induction in response to LT challenge. Our findings suggest a complex interaction of events and/or mediators in LT‐treated mice with the neutrophil as a central player in induction of a profound and rapid inflammatory response to toxin.

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Antiplatelet Activities of Anthrax Lethal Toxin Are Associated with Suppressed p42/44 and p38 Mitogen‐Activated Protein Kinase Pathways in the Platelets

Cited by 46 publications

References 54 publications

Acquired coagulant factor VIII deficiency induced byBacillus anthracislethal toxin in mice

Acquired coagulant factor VIII deficiency induced byBacillus anthracislethal toxin in mice

Anthrax Toxins

Frontline Science: Anthrax lethal toxin-induced, NLRP1-mediated IL-1β release is a neutrophil and PAD4-dependent event

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