Novel phosphatidylethanolamine derivatives accumulate in circulation in hyperlipidemic ApoE−/− mice and activate platelets via TLR2

Biswas, Sudipta; Liang, Xuefang; Panigrahi, Soumya; Zimman, Alejandro; Wang, Hua; Yakubenko, Valentin P.; Byzova, Tatiana V.; Salomon, Robert G.; Podrez, Eugene A.

doi:10.1182/blood-2015-08-664300

Cited by 43 publications

(58 citation statements)

References 44 publications

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“…In vitro studies have demonstrated that oxPC CD36 induce the innate immune signaling pathway in platelets via TIRAP-MyD88-IRAKs-TRAF6, followed by c-Src and Fyn activation. Our current findings and recent observations 9 indicate that TLR2 is involved in the recognition of a wide range of oxidation derived epitopes, and it is a key player in prothrombotic phenotype associated with hyperlipidemia.…”

Section: Introductionsupporting

confidence: 74%

“…Src −/− and Lyn −/− mice were generated as reported earlier. 9 We generated ApoE −/− /CD36 −/− by crossing ApoE −/− with CD36 −/− mice as described 10 , and ApoE −/− /TLR2 −/− and ApoE −/− /TLR6 −/− mice by crossing ApoE −/− with TLR2 −/− or TLR6 −/− mice respectively. We further crossed ApoE −/− /CD36 −/− mice to ApoE −/− /TLR2 −/− or ApoE −/− /TLR6 −/− mice to generate ApoE −/− /CD36 −/− /TLR2 −/− or ApoE −/− /CD36 −/− /TLR6 −/− triple knockout mice.…”

Section: Methodsmentioning

confidence: 99%

“…The HEK-Blue™-hTLR2 cells and HEK-Blue™-hTLR9 cells that stably co-express human TLR2 or human TLR9 respectively along with NF-κB-inducible SEAP (secreted embryonic alkaline phosphatase) reporter gene were cultured as described before 9 for 16–18 hours in the presence of indicated agonists. NF-κB-induced SEAP activity was assessed in the culture supernatant using QUANTI-Blue™ and reading at OD 630 nm as per manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

“…22–25 Moreover, we have recently reported that platelets can also respond to oxidation specific epitopes via TLRs. 9, 17 Our observation of the strong thromboprotective effect of TLR2 deficiency in hyperlipidemic mice 9 prompted us to hypothesize that TLR2 may have a role in oxPC CD36 induced platelet activation.…”

Section: Introductionmentioning

confidence: 99%

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TLR2 Plays a Key Role in Platelet Hyperreactivity and Accelerated Thrombosis Associated With Hyperlipidemia

Biswas

Zimman

Gao

et al. 2017

Circulation Research

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Rationale Platelet hyperreactivity, which is common in many pathological conditions, is associated with increased atherothrombotic risk. The mechanisms leading to platelet hyperreactivity are complex and not yet fully understood. Objective Platelet hyperreactivity and accelerated thrombosis, specifically in dyslipidemia, have been mechanistically linked to accumulation in the circulation of a specific group of oxidized phospholipids (oxPCCD36) that are ligands for the platelet pattern-recognition receptor CD36. In the current manuscript, we tested whether the platelet innate immune system contributes to responses to oxPCCD36 and accelerated thrombosis observed in hyperlipidemia. Methods and Results Using in vitro approaches, as well as platelets from mice with genetic deletion of MyD88 or TLRs, we demonstrate that TLR2 and TLR6 are required for the activation of human and murine platelets by oxPCCD36. oxPCCD36 induce formation of CD36/TLR2/TLR6 complex in platelets and activate downstream signaling via TIRAP-MyD88-IRAK1/4-TRAF6, leading to integrin activation via the SFK-Syk-PLCγ2 pathway. Intravital thrombosis studies using ApoE−/− mice with genetic deficiency of TLR2 or TLR6 have demonstrated that oxPCCD36 contribute to accelerated thrombosis specifically in the setting of hyperlipidemia. Conclusions Our studies reveal that TLR2 plays a key role in platelet hyperreactivity and the prothrombotic state in the setting of hyperlipidemia by sensing a wide range of endogenous lipid-peroxidation ligands and activating innate immune signaling cascade in platelets.

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Section: Introductionsupporting

confidence: 74%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

TLR2 Plays a Key Role in Platelet Hyperreactivity and Accelerated Thrombosis Associated With Hyperlipidemia

Biswas

Zimman

Gao

et al. 2017

Circulation Research

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“…Genetic manipulation of this locus results in an increased number of circulating and hyper-reactive platelets that may be more susceptible to the proinflammatory effects of hypercholesterolemia. 16 Finally, these findings also suggest the intriguing possibility that therapies targeting dsyregulated megakaryopoiesis and thrombopoiesis may also modulate the risk of atherothrombosis and MI.…”

Section: Arfmentioning

confidence: 97%

Cdkn2a Orchestrates Platelet Production and Reactivity in Atherosclerosis

Schwertz

Rondina

2016

Circ Cardiovasc Genet

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Innate immune receptors in platelets and platelet-leukocyte interactions

Dib

Quirino-Teixeira

Merij

et al. 2020

Journal of Leukocyte Biology

121

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Platelets are chief cells in hemostasis. Apart from their hemostatic roles, platelets are major inflammatory effector cells that can influence both innate and adaptive immune responses. Activated platelets have thromboinflammatory functions linking hemostatic and immune responses in several physiological and pathological conditions. Among many ways in which platelets exert these functions, platelet expression of pattern recognition receptors (PRRs), including TLR, Nod-like receptor, and C-type lectin receptor families, plays major roles in sensing and responding to pathogen-associated or damage-associated molecular patterns (PAMPs and DAMPs, respectively). In this review, an increasing body of evidence is compiled showing the participation of platelet innate immune receptors, including PRRs, in infectious diseases, sterile inflammation, and cancer. How platelet recognition of endogenous DAMPs participates in sterile inflammatory diseases and thrombosis is discussed. In addition, platelet recognition of both PAMPs and DAMPs initiates platelet-mediated inflammation and vascular thrombosis in infectious diseases, including viral, bacterial, and parasite infections. The study also focuses on the involvement of innate immune receptors in platelet activation during cancer, and their contribution to tumor microenvironment development and metastasis. Finally, how innate immune receptors participate in platelet communication with leukocytes, modulating leukocyte-mediated inflammation and immune functions, is highlighted. These cell communication processes, including platelet-induced release of neutrophil extracellular traps, platelet Ag presentation to T-cells and platelet modulation of monocyte cytokine secretion are discussed in the context of infectious and sterile diseases of major concern in human health, including cardiovascular diseases, dengue, HIV infection, sepsis, and cancer.

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Novel phosphatidylethanolamine derivatives accumulate in circulation in hyperlipidemic ApoE−/− mice and activate platelets via TLR2

Abstract: Key Points CAP-PEs, a novel type of oxidatively modified phospholipids, are present in vivo. CAP-PEs can activate platelets via TLRs by inducing a cross-talk between innate immunity and integrin activation signaling pathways.

Cited by 43 publications

References 44 publications

TLR2 Plays a Key Role in Platelet Hyperreactivity and Accelerated Thrombosis Associated With Hyperlipidemia

TLR2 Plays a Key Role in Platelet Hyperreactivity and Accelerated Thrombosis Associated With Hyperlipidemia

Cdkn2a Orchestrates Platelet Production and Reactivity in Atherosclerosis

Innate immune receptors in platelets and platelet-leukocyte interactions

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