Autoantibody against integrin αvβ3 contributes to thrombocytopenia by blocking the migration and adhesion of megakaryocytes

Abstract

Background The pathogenesis of immune thrombocytopenia (ITP) has not been fully clarified. Anti-αvβ3 integrin autoantibody is detected in chronic ITP patients, but its contribution to ITP is still unclear. Objectives To clarify the potential role of anti-αvβ3 integrin autoantibody in chronic ITP and the related mechanism. Methods Relationship between levels of anti-αvβ3 autoantibody and platelets in chronic ITP patients was evaluated. The influence of anti-αvβ3 antibody on megakaryocyte (MK) survival, differentiation, migration and adhesion was assessed, and the associated signal pathways were investigated. Platelet recovery and MKs' distribution were observed in an ITP mouse model pretreated with different antibodies. Result In this study, we showed that the anti-αvβ3 autoantibody usually coexists with anti-αIIbβ3 autoantibody in chronic ITP patients, and patients with both autoantibodies have lower platelets. In in vitro studies, we showed that the anti-αvβ3 antibody had no significant effect on the survival and proliferation of MKs, whereas it decreased formations of proplatelet significantly. Anti-αvβ3 antibody impeded stromal cell derived facor-1 alpha (SDF-1α)- mediated migration and inhibited the phosphorylation of protein kinase B. Anti-αvβ3 antibody significantly inhibited MKs' adhesion to endothelial cells and Fibrogen. The phosphorylation of focal adhesion kinase and proto-oncogene tyrosine-protein kinase Src induced by adhesion was inhibited when MKs were pretreated with anti-αvβ3 antibody. In in vivo studies, we showed that injection with anti-α antibody delayed platelet recovery in a mouse model of ITP. Conclusions These findings demonstrate that the autoantibody against integrin α β may aggravate thrombocytopenia in ITP patients by impeding MK migration and adhesion to the vascular niche, which provides new insights into the pathogenesis of ITP.

Deficiency of platelet adhesion molecule CD226 causes megakaryocyte development and platelet hyperactivity

“…Many immune regulatory molecules and cytokines are also expressed on platelets (eg, Toll‐like receptors, P‐selectin, CD40L, interleukin‐1β, and transforming growth factor‐β) and have the ability to interact with immune cells, with integrin family member playing key roles, 28,29 such as β2 integrin modulating platelet caspase activation and life span in mice 30 . Autoantibody to α v β 3 was detected in immune thrombocytopenia patients and contributes to thrombocytopenia by blocking the adhesion and migration of MKs 31 . Adhesion and degranulation‐promoting adaptor protein regulates integrins α Ⅱb β 3 and α 1 β 2 in platelets and α L β 2 (LFA‐1, CD226‐associated molecule) in T cells, 32 suggesting that integrin‐associated molecules play key roles both in leukocytes and platelets.…”

The role of integrins in melanoma: a review

“…In addition to their role in primary tumor growth, integrins are also important mediators of metastasis 28 . They are involved in multiple steps that help in tumor spread: (i) degradation of the basement membrane barrier for tumor cells, 29‐35 (ii) angiogenesis for tumor survival at the primary site, 36‐39 (iii) as integral components of exosomes (small extracellular molecules detached from the primary tumor into the circulation), 40‐43 (iv) intravasation of tumor cells into the circulation, 36 and (v) implantation at the metastatic niche 44,45 …”

“…Binding of ɑvβ3 to the exposed RGD motif further stimulates MMP‐2 expression, thereby perpetuating the cycle and promoting tumor invasion. Zeng et al 34 . noted that blocking integrins β1 and ɑvβ3 with antibodies resulted in decreased tumor cell adhesion and migration.…”

Pathophysiological Mechanisms Leading to Low Platelet Count in Immune Thrombocytopenia

“…Along with these abnormalities, Zeng and col. 54 added autoantibodies targeting the vitronectin receptor, to the list of factors responsible for the interference between megakaryocyte adhesion to the vascular niche, and potentially contributing to impair platelet production in ITP.…”