Snake Venom Disintegrin Inhibits the Activation of Toll-Like Receptors and Alleviates Sepsis through Integrin alphaVbeta3 Blockade.

Chun-Chieh Hsu,Hui-Chin Peng,Woei-Jer Chuang,Chien-Hsin Chang,Ching-Hu Chung,Tur-Fu Huang

doi:10.1038/srep23387

Chun-Chieh Hsu, Hui-Chin Peng + Show 4 more

Open Access

https://doi.org/10.1038/srep23387

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Abstract

Bacterial infection-induced sepsis is the leading cause of septic inflammatory disease. Rhodostomin (Rn), a snake venom disintegrin, was previously reported to interact with the αVβ3 integrin and the TLR4 on phagocyte in attenuating LPS-induced endotoxemia. In this report, we further evaluated the effects of Rn on TLR2-activated monocytes and its in vivo efficacy. Rn effectively suppressed the adhesion, migration, and cytokine release of Pam3CSK4-activated THP-1 cells. Rn specifically bound to integrin αVβ3 of TLR2-activated THP-1. Integrin αV and Akt siRNA transfection both restrained Pam3CSK4-elicited cytokine release. Rn decreased the Pam3CSK4-induced phosporylation of MAPKs, degradation of IκB and activation of FAK, Akt, c-Src and Syk. The Pam3CSK4-induced translocation of MyD88, a central adaptor of TLR2, to the cell membrane was also inhibited by Rn treatment. In the polymicrobial inflammatory caecal ligation and puncture model, Rn significantly reduced pro-inflammatory cytokine and chemokine release, alleviated tissue injury and elevated survival rate in vivo. Taken together, in addition to inhibiting the activation of TLR4, Rn exhibits anti-inflammatory activity through antagonizing the activation of phagocytes and interrupting the crosstalk between αVβ3 and TLR2-dependent signaling pathways.

Highlights

The innate immune system is the first line to identify and defense microbial pathogens protecting the host from infection[1]
We previously reported that a disintegrin, rhodostomin (Rn), interrupts the LPS-induced activation of phagocytes through interaction with α Vβ 3 integrin of monocytes/macrophages, contributing to its anti-inflammatory protection in LPS- induced endotoxemia in vivo[9]
We observed that a snake venom disintegrin, Rn, suppresses the inflammatory responses of TLR2-stimulated monocytes

Summary

Introduction

The innate immune system is the first line to identify and defense microbial pathogens protecting the host from infection[1]. After TLR4 activation by LPS, the activation of mitogen-activated protein kinase (MAPK) signaling pathway and transcription factor, nuclear factor κ B (NFκ B) are triggered in phagocytes[3]. Integrin is another important receptor family of immune cells. We previously reported that a disintegrin, rhodostomin (Rn), interrupts the LPS-induced activation of phagocytes through interaction with α Vβ 3 integrin of monocytes/macrophages, contributing to its anti-inflammatory protection in LPS- induced endotoxemia in vivo[9]. We used recombinant Rn14 to explore the anti-inflammatory effect of disintegrin on Pam3CSK4 (a TLR2-specific agonist)-induced activation of phagocytes and the mechanism involved. Its in vivo anti-inflammatory efficacy in a polybacterial infection caecal ligation and puncture (CLP)-model was examined

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