Natural IgM antibodies inhibit microvesicle-driven coagulation and thrombosis

Abstract

Thrombosis and the complications associated with it are a major cause of morbidity and mortality worldwide. Microvesicles (MVs), a class of extracellular vesicles, are increasingly recognized as mediators of coagulation and biomarkers of thrombotic risk. Thus, identifying factors targeting MV-driven coagulation may help in the development of novel antithrombotic treatments. We have previously identified a subset of circulating MVs that is characterized by the presence of oxidation-specific epitopes and bound by natural IgM antibodies targeting these structures. Here, we investigated whether natural IgM antibodies, which are known to have important anti-inflammatory house-keeping functions, inhibit the procoagulatory properties of MVs. We found that the extent of plasma coagulation is inversely associated with the levels of both free and MV-bound endogenous IgM. Moreover, the oxidation epitope-specific natural IgM antibody LR04, which recognizes malondialdehyde adducts, reduced MV-dependent plasmatic coagulation and whole blood clotting without affecting thrombocyte aggregation. Intravenous injection of LR04 protected mice from MV-induced pulmonary thrombosis. Of note, LR04 competed the binding of coagulation factor X/Xa to MVs, providing a mechanistic explanation for its anticoagulatory effect. Thus, our data identify natural IgM antibodies as hitherto unknown modulators of MV-induced coagulation in vitro and in vivo and their prognostic and therapeutic potential in the management of thrombosis.

Extracellular Vesicles as Drivers of Immunoinflammation in Atherothrombosis

“…B-cell-derived natural IgM recognizes EVs bearing oxidation-specific epitopes and represses their inflammatory signaling and pathological endeavors [ 141 ]. Moreover, natural IgM antibodies inhibit MV-driven coagulation and thrombosis [ 142 ].…”

“…Under in vitro simulated conditions of coagulopathy, EV from different cellular origins (EC and platelet) and at distinct concentrations showed a divergent but procoagulant effect within the coagulation process [ 196 ]. Numerous studies have dissected in vitro and in vivo the procoagulant effect of EVs, mainly MVs, leading to thrombosis [ 142 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 ]. Procoagulant EVs within the necrotic core of atherosclerotic plaques provoke the burst of the coagulation cascade upon plaque rupture [ 169 ] being TF + -MVs the main initiators [ 208 , 209 , 210 ].…”

Extracellular Vesicles in Blood: Sources, Effects, and Applications

“…Circulating IgM antibodies have been found to be part of the complex regulatory system of EV functioning, controlling the coagulant capacity of EVs. Indeed, endogenous IgM antibodies were found to bind to oxidation-specific epitopes in EVs and to modulate EV-mediated coagulation and thrombosis in in vitro and in vivo experiments [ 94 ]. Similarly, circulating EVs participate in vascular homeostasis.…”

Adaptive tolerance: Protection through self‐recognition

“…[ 26,88 ] For instance, it has been shown that nIgM is capable of removing oxidized lipids (oxLDL), advanced glycation end products (AGE), nucleic acids and other potentially harmful self‐molecules as well as prevent thrombosis. [ 27,89,90 ] In addition, several studies also reported cross‐reactivity of nIgM with insulin, immunoglobulins and LPS. [ 91,92 ] Moreover, studies exploiting transgenic mouse models unable to secrete IgM (sIgM‐/‐) have shown that loss of sIgM results in numerous diseases including atherosclerosis and autoimmunity most likely due to the accumulation of altered self‐molecules.…”