TLR4-dependent upregulation of the platelet NLRP3 inflammasome promotes platelet aggregation in a murine model of hindlimb ischemia |
| |
Authors: | Sebastian Vogel Pranav Murthy Xiangdong Cui Michael T. Lotze Herbert J. Zeh Ulka Sachdev |
| |
Affiliation: | Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA |
| |
Abstract: | Platelets play a critical role in the pathophysiology of peripheral arterial disease (PAD). The mechanisms by which muscle ischemia regulates aggregation of platelets are poorly understood. We have recently identified the Nod-like receptor nucleotide-binding domain leucine rich repeat containing protein 3 (NLRP3) expressed by platelets as a critical regulator of platelet activation and aggregation, which may be triggered by activation of toll-like receptor 4 (TLR4). In this study, we performed femoral artery ligation (FAL) in transgenic mice with platelet-specific ablation of TLR4 (TLR4 PF4) and in NLRP3 knockout (NLRP3?/?) mice. NLRP3 inflammasome activity of circulating platelets, as monitored by activation of caspase-1 and cleavage of interleukin-1β (IL-1β), was upregulated in mice subjected to FAL. Genetic ablation of TLR4 in platelets led to decreased platelet caspase 1 activation and platelet aggregation, which was reversed by the NLRP3 activator Nigericin. Two weeks after the induction of FAL, ischemic limb perfusion was increased in TLR4 PF4 and NLRP3?/? mice as compared to control mice. Hence, activation of platelet TLR4/NLRP3 signaling plays a critical role in upregulating platelet aggregation and interfering with perfusion recovery in muscle ischemia and may represent a therapeutic target to improve limb salvage. |
| |
Keywords: | Platelets NLRP3 Hindlimb ischemia Peripheral arterial disease ASC apoptosis-associated speck-like protein containing a CARD FAL femoral artery ligation IL-1β interleukin-1β NLRP3 nucleotide-binding domain leucine rich repeat containing protein 3 PAD peripheral arterial disease TLR4 toll-like receptor 4 WT wild-type |
本文献已被 ScienceDirect 等数据库收录! |