MOSPD2 regulates the activation state of αLβ2 integrin to control monocyte migration: applicability for treatment of chronic inflammatory diseases

Monocytes are innate immune cells that drive the chronicity of various inflammatory diseases. Monocyte migration to inflamed tissues involves multiple steps of interaction with the vascular endothelium and the extracellular matrix (ECM), a process 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 inflammation. Investigating MOSPD2's mechanism of action, we assessed whether it plays a role in regulating integrin activation and monocyte adhesion. Data show that silencing of MOSPD2 expression in the THP-1 monocytic cell line significantly increased cell adhesion to various ECM molecules. Employing IW-601, a humanized anti-human MOSDP2 monoclonal antibody, on primary human monocytes increased adhesion to ECM molecules as well as to adhesion molecules. At the molecular level, silencing of MOSPD2 or blocking MOSPD2 using IW-601 led to a transition in integrin αLβ2 (CD11a/CD18, LFA-1) conformation into an active high-affinity binding form and to the induction of adhesion-associated signaling pathways. Co-immunoprecipitation experiments showed that MOSPD2 binds integrin-β2 (CD18), but not integrin-β1 (CD29). Our results reveal a novel mechanism controlling monocyte migration, in which MOSPD2 acts as an adhesion checkpoint that governs the balance between monocyte adhesion and release. By demonstrating the inhibitory effect of IW-601 on the migration of primary monocytes isolated from patients with chronic inflammatory diseases, we provide proof of concept for translating MOSPD2's mechanism into a potential treatment for inflammatory diseases, further supported by in vivo data in models of RA and IBD.