Netrin-1 suppresses CCL2-driven macrophage migration: implications for modulating vascular inflammation and aortic sinus enlargement in hyperlipidaemic mice.

BACKGROUND

Atherosclerosis is driven by sustained recruitment and accumulation of monocytes and macrophages within arterial walls through chemokine-mediated pathways. Netrin-1, an immunomodulatory molecule originally identified in neural development, has emerged as a potential regulator of vascular inflammation, though its precise effects on chemokine-driven leukocyte migration remain undefined.

METHODS

We investigated netrin-1 effects on macrophage migration in vitro using real-time impedance-based assays and assessed systemic effects in vivo through intravital microscopy and aortic sinus histology in an inflammation-induced model.

RESULTS

Netrin-1 selectively inhibited CCL2-driven macrophage migration in vitro, reducing migration when combined with the chemokine compared to chemokine alone. In an acute inflammation mouse model, systemic netrin-1 pre-treatment showed a trend toward the decrease of monocyte adhesion and transmigration into the tissue while increasing rolling interactions, suggesting impaired firm adhesion and diapedesis. Importantly, hyperlipidaemic LDLR-/- mice presented enlarged aortic sinus after being fed a high-fat diet, and this enlargement was not observed when netrin-1 was continuously administered via osmotic minipumps.

CONCLUSIONS

Our data suggests that systemic netrin-1 selectively inhibits chemokine-driven monocyte migration in vitro, with potential implications for reducing vascular inflammatory cell recruitment, an important component of atherogenesis.