Neuronal CCL2 expression drives inflammatory monocyte infiltration into the brain during acute virus infection

Charles L Howe; Reghann G. LaFrance-Corey; Emma N Goddery; Kanish Mirchia

The multistep process of leukocyte entry into the central nervous system is predominantly controlled by chemokines [12] . In particular, inflammatory monocyte trafficking is thought to depend upon C-C motif chemokine receptor type 2 (CCR2) signaling in response to C-C motif chemokine ligand 2 (CCL2) [13] , though the specific details of this dependency vary with viral pathogen. For example, CCR2-deficient mice exhibited reduced monocyte recruitment to the brain but increased mortality during West Nile virus encephalitis [14] and this effect was differentially regulated by CCL2 and CCL7, another CCR2 ligand [15] . In a model of Japanese encephalitis virus infection, mice deficient in CCR2 had reduced monocyte infiltration and reduced mortality, whereas CCL2-deficient animals exhibited increased monocyte infiltration and increased mortality [16] . Both CCL2-and CCR2-deficient mice with mouse hepatitis virus encephalitis had reduced monocyte infiltration, but only CCR2-deficient mice exhibited increased mortality [17, 18] . Likewise, mice with CCR2-deficient hematopoietic cells mounted a reduced monocyte response to herpes simplex virus 1 infection and exhibited increased mortality [19] . These studies clearly support a role for the CCR2:CCL2 axis in trafficking of inflammatory monocytes to the brain during viral encephalitis. However, the specific cellular source of the CCL2 is not identified in any of this work. In the current study we demonstrate that inflammatory monocyte infiltration into the brain during acute TMEV infection requires CCR2 and that neurons are a key source of CCL2 driving this trafficking during the earliest stages of infection.