Abstract
Monocytes exist in two major populations, termed Ly6Chi and Ly6Clow monocytes. Compared to Ly6Chi monocytes, less is known about Ly6Clow monocyte recruitment and mechanisms involved in the recruitment of this subset. Furthermore, the role of Ly6Clow monocytes during infections is largely unknown. Here, using intravital microscopy, we demonstrate that Ly6Clow 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 Ly6Clow monocytes. Furthermore, TNFR signaling is essential for the recruitment through enhancing VLA4 expression on Ly6Clow monocytes. Interestingly, the recruited Ly6Clow 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 Ly6Clow monocytes to the brain and highlights important properties of this subset during infection.
Highlights
Derived from the bone marrow, monocytes are a heterogeneous population of leukocytes in the blood and play a central role during infection and inflammation [1, 2]
In contrast to the recruitment of Ly6Chi monocytes shown in other infection models, we observed the predominant recruitment of Ly6Clow monocytes to the brain post-capillary venules during intravenous infection with C. neoformans, a fungal pathogen
We further demonstrate that TNFR signaling plays an essential role during Ly6Clow monocyte recruitment through enhancing VLA4 expression on monocytes
Summary
Derived from the bone marrow, monocytes are a heterogeneous population of leukocytes in the blood and play a central role during infection and inflammation [1, 2]. Ly6Chi monocytes are rapidly recruited to tissues in a CCR2-dependent manner [2, 6]. They secrete high levels of proinflammatory cytokines and differentiate into inflammatory dendritic cells and inflammatory macrophages, contributing to local and systemic inflammation [2]. Recent data suggest that Ly6Clow monocytes are recruited to sites of inflammation, playing an anti-inflammatory role [9, 10] or proinflammatory role [11,12,13]
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