The role of TLR4 in pathophysiology of antiphospholipid syndrome‐associated thrombosis and pregnancy morbidity

Abstract

SummaryThe antiphospholipid syndrome (APS) is an autoimmune disease characterized by the clinical features of recurrent thrombosis in the venous or arterial circulation and fetal losses. Antiphospholipid antibodies (aPL), particularly against the phospholipid binding protein beta-2 glycoprotein I (b2GPI), play an important role in APS pathological mechanisms. aPL can activate intracellular signal transduction in a b2GPI-dependent manner to induce inflammatory responses, and promote hypercoagulable state and recurrent spontaneous abortion when b2GPI is associated with the cell surface receptor. In vivo and in vitro studies show that Annexin A2 (ANXA2) is the high affinity receptor that connects b2GPI to the target cells. However, ANXA2 is not a transmembrane protein and lacks an intracellular signal transduction pathway. Growing evidences suggest that the transmembrane protein toll-like receptor 4 (TLR4) might act as an 'adaptor' for intracellular signal transduction. This review focuses on the role of TLR4 and its signalling pathway in APS pathological mechanisms which will help us better understand the pathological processes of this syndrome.

Cellular fibronectin containing extra domain A promotes arterial thrombosis in mice through platelet Toll-like receptor 4

“…Recent studies have suggested a role for TLR4 signaling in promoting thrombosis, [21][22][23][24] and the EDA segment of cFn, but not other domains, is known to activate human TLR4 expressed in HEK293 cells via myeloid differentiation-2. 16 Interestingly, polymorphisms in human TLR4 have been associated with increased atherothrombotic risk.…”

“…Several previous studies have demonstrated that cellular Fn-EDA1 interacts with the innate immune receptor TLR4, which has been shown to play a role in modulating thrombosis in the presence of its exogenous and endogenous ligands. [21][22][23][24]30 To determine whether TLR4 contributes to cellular Fn-EDA1-mediated accelerated arterial thrombosis, we generated Fn-EDA 1/1 mice on a TLR4-deficient background (Fn-EDA…”

“…16 Using specific TLR4 inhibitors, we and others have demonstrated that cellular Fn-EDA1 activates TLR4 signaling. [16][17][18][19][20] Several studies have suggested a role for TLR4 signaling in promoting thrombosis, [21][22][23][24] particularly in the context of endotoxemia and sepsis. 22,23 Recently, extracellular histones have been shown to induce platelet aggregation and thrombin generation through TLR4 and TLR2, 21 suggesting an lipopolysaccharide (LPS)-independent role for TLR4 in thrombosis that is mediated by endogenous ligands.…”

TLR4 is involved in the pathogenic effects observed in a murine model of antiphospholipid syndrome

“…and 174 the right carotid artery was exposed. A 1 × 1.5 mm strip of in vitro assays, TLR4 plays important roles in aPL-induced TF 308 activity/expression [24,25]. Therefore, we first measured 309 the TF activity in peritoneal macrophages and carotids 310 harvested from experimental animals injected with NR-IgG, 311 anti-β2GPI, or IgG-APS.…”

Relationship between TLR4 and MCP2 expression levels and habitual abortion

“…The birth of a new life is an extremely complex and regulated process, and involves the immunological interactions between maternal and paternal gametes, the maternal immunological function, expression of genes inherited from both parents, and chromosome structure (Wilding et al, 2004;Burrough et al, 2011;Turner et al, 2012;Xie et al, 2014). At present, habitual abortion not only seriously affects the patient's psychological and physiological health, but the quality of life of the patient's family.…”