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PI3K/AKT and CD40L Signaling Regulate Platelet Activation and Endothelial Cell Damage in Sepsis

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Abstract

Platelets contribute to inflammation and their activation has been suggested as versatile effectors of sepsis. Activation of platelets promotes secretion of CD40L that induces sepsis and multiple organ dysfunction syndrome (MODS). However, the mechanisms regulate platelet-derived CD40L are not fully understood. Activation of PI3K/Akt pathway has been reported as a key component of sepsis, whereas the role of PI3K/Akt pathway in platelet-derived CD40L is unknown. In this study, we identified PI3K/Akt pathway as a key regulator of CD40L secretion by platelets. Significantly, inhibition of PI3K/Akt pathway by Ly294002 attenuated platelet activation and CD40L production. Moreover, PI3K/Akt pathway blocking suppresses vascular endothelial cells in vivo. Furthermore, the expression of biomarkers that represent the severity of sepsis, such as ICAM-1, VCAM-1, and E-selectin, was also suppressed by Ly294002. Altogether, our results confirm the pivotal role of PI3K/Akt pathway in sepsis and its inhibition might be a potential therapeutic target.

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Acknowledgments

We thank Zhaoxiang Zhang (Shanghai Gefan Biotechnology CO. LTD) for expert technical assistance.

Funding

This work was supported by the Natural Science Foundation of Yichang of Hubei Province of China (A16-301-13), Chinese National Natural Science Foundation (81501045), and Chinese National Natural Science Foundation (81471839).

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Authors and Affiliations

  1. Department of Critical Care Medicine, the People’s Hospital of China Three Gorges University, Yichang, 443110, Hubei, China

    Peng Wan, Xiang Tan, Yan Xiang, Huasheng Tong & Min Yu

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  1. Peng Wan
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  2. Xiang Tan
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  3. Yan Xiang
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Correspondence to Min Yu.

Ethics declarations

The ethical approval of our experiments was approved from Human Subjects Institutional Review Board of China Three Gorges University (No. 2016014). Written informed consent was obtained from all patients or patients’ relatives, who were aware of the details of this experiment, including the aims and methods. Our animal studies were approved by the Animal Ethical Committee of Shandong University and were in accordance with the Institutional Animal Care and Use Committee of Shandong University.

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The authors declare that they have no conflict of interest.

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Wan, P., Tan, X., Xiang, Y. et al. PI3K/AKT and CD40L Signaling Regulate Platelet Activation and Endothelial Cell Damage in Sepsis. Inflammation 41, 1815–1824 (2018). https://doi.org/10.1007/s10753-018-0824-5

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