MOSPD2 regulates the activation state of αLβ2 integrin to control monocyte migration

Abstract

Abstract Monocytes are innate immune cells that drive the chronicity of various inflammatory diseases, making them an attractive target for therapeutic intervention. Monocyte migration to inflamed tissues involves multiple steps of interaction with the vascular endothelium and the extra-cellular matrix (ECM), a process mainly mediated through conformational transitions in cell surface integrins. We previously described Motile sperm domain-containing protein 2 (MOSPD2) as a surface protein expressed on myeloid cells that is essential for the migration of monocytes and a key regulator of inflammatory disease pathogenesis. Therefore, a possible role for MOSPD2 in regulating adhesion and integrin activation in monocytes was assessed. Silencing of MOSPD2 expression in THP-1 monocytic cell line significantly increased the adhesion of monocytes to various ECM ligands of integrins. Employing VB-601, a humanized anti-human MOSDP2 monoclonal antibody, on wild-type THP-1 cells or primary human CD14 monocytes similarly increased cell adhesion to ECM ligands as well as adhesion molecules. At the molecular level, silencing of MOSPD2 or blocking MOSPD2 using VB-601 led to a transition in integrin αLβ2 conformation into active high affinity binding-form and to the phosphorylation of adhesion-associated pathways. Co-precipitation experiments show that MOSPD2 binds integrin-β2, but not integrin-β1. Our results reveal a novel regulatory mechanism on monocyte migration in which MOSPD2 governs the balance between monocyte adhesion and release from adhesion molecules and ECM. Targeting MOSPD2 has the potential to treat inflammatory diseases by stemming monocyte infiltration into inflamed tissues.