VCAM1/VLA4 interaction mediates Ly6C(low) monocyte recruitment to the brain in a TNFR signaling dependent manner during fungal infection

Monocytes exist in two major populations, termed Ly6C(hi) and Ly6C(low) monocytes. Compared to Ly6C(hi) monocytes, less is known about Ly6C(low) monocyte recruitment and mechanisms involved in the recruitment of this subset. Furthermore, the role of Ly6C(low) monocytes during infections is largely unknown. Here, using intravital microscopy, we demonstrate that Ly6C(low) monocytes are predominantly recruited to the brain vasculature following intravenous infection with Cryptococcus neoformans, a fungal pathogen causing meningoencephalitis. The recruitment depends primarily on the interaction of VCAM1 expressed on the brain endothelium with VLA4 expressed on Ly6C(low) monocytes. Furthermore, TNFR signaling is essential for the recruitment through enhancing VLA4 expression on Ly6C(low) monocytes. Interestingly, the recruited Ly6C(low) monocytes internalized C. neoformans and carried the organism while crawling on and adhering to the luminal wall of brain vasculature and migrating to the brain parenchyma. Our study reveals a substantial recruitment of Ly6C(low) monocytes to the brain and highlights important properties of this subset during infection.