357 ISSN 0006-3509, Biophysics, 2018, Vol. 63, No. 3, pp. 357–364. © Pleiades Publishing, Inc., 2018. Original Russian Text © A.S. Maiorov, T.O. Shepelyuk, F.A. Balabin, A.A. Martyanov, D.Y. Nechipurenko, A.N. Sveshnikova, 2018, published in Biofizika, 2018, Vol. 63, No. 3, pp. 475–483. Modeling of Granule Secretion upon Platelet Activation through the TLR4-Receptor A. S. Maiorov a, b, c , T. O. Shepelyuk a, b, c, d , F. A. Balabin b , A. A. Martyanov a, b, c , D. Y. Nechipurenko a, b, c, *, and A. N. Sveshnikova a, b, c a Department of Physics, Moscow State University, Moscow, 119991 Russia b Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, 119991 Russia c National Medical Research Center of Pediatric Hematology, Oncology, and Immunology, Moscow, 117197 Russia d Faculty of Basic Medicine, Moscow State University, Moscow, 119991 Russia *e-mail: ne4ipur@gmail.com Received December 5, 2017; in final form, March 8, 2018 Abstract⎯This paper presents the mathematical modeling of the possibility of blood platelets activation by lipopolysaccharides, which are components of the cell wall of gram-negative bacteria, through the toll-like receptor TLR4. We have developed both complete and reduced models of the platelet signaling cascade trig- gered by TLR4 considering the known kinetics of intracellular signaling enzymes and the contents of the pro- teins that participate in the TLR4 signaling cascade in human platelets. The results of our simulation show that the concentration of the soluble CD14 protein, which is necessary for the activation of platelets by lipo- polysaccharides via TLR4, is insufficient for platelet activation in the blood of healthy donors. Thus, our results suggest that blood platelets can be activated by lipopolysaccharides through TLR4 only in cases of strong activation of the immune system accompanied by an increase in CD14 concentration in the blood. Keywords: intracellular signaling, lipopolysaccharides, Escherichia coli, blood coagulation DOI: 10.1134/S0006350918030144 The body’s reaction to bacterial infection in the bloodstream is a complex response involving cells and components of the immune system, blood coagula- tion, and the endothelium, as well as regulatory organs. Even the interaction of one of these systems, the blood-coagulation system, with a bacterial infec- tion includes multiple processes. Platelets aggregate around bacteria and are activated by the bacteria. They then consume bacteria by phagocytosis, recognize the bacterial patterns, and produce anti-microbial agents. In all the cases mentioned above, platelets trigger the immune response. In turn, the bacteria form colonies on the inflamed endothelium and thrombus, which allows them to attach to the cell wall in the blood- stream. Colonies of bacteria can also “hide” inside the thrombus from the immune system. At the same time, all the above-mentioned responses of platelets at the molecular level are specific not only for the genus, but sometimes even for the strain of pathogenic bacte- ria [1]. The most common experimental model of bacte- rial infection is the direct introduction into the blood- stream of the components of the cell wall of gram-neg- ative bacteria; that is, lipopolysaccharides (LPS) [2]. Although this leads to activation of blood coagulation, the contribution of platelet activation to this process has not been studied [3]. While most researchers observe platelet activation in the presence of patho- genic E. coli strains, the molecular mechanism of platelet activation in this case also remains unknown [4, 5]. Some studies indicate activation of platelets via FcγRIIa-receptor [4, 5]. One of the possible paths for the interaction of immune-system cells and E. coli is the activation of Toll-like receptors (TLR), which interact with LPS [6]. TLR4, as the main LPS receptor, triggers the acti- vation of the transcription factor NFκB in the nucle- ated cells. NFκB mediates most activation responses [7]. Although TLR4 receptors are present on platelet membranes [8] their potential effect remains unknown, as platelets have no cell nucleus. It has been suggested that NFκB may promote protein translation based on platelet mRNA [9, 10]. Existing mathematical models of TLR4 signaling were designed for nucleated cells. A key indicator of cell activation in these models is the synthesis of pro- teins such as TNFα and IκBα [11]. As a result, such Abbreviations: LPS, lipopolysaccharide(s); TLR, toll-like recep- tor; LBP, LPS-binding protein (the plasma protein that binds LPS and delivers it to the CD14 protein). CELL BIOPHYSICS