IFN-γ triggers CCR2-independent monocyte entry into the brain during systemic infection by virulent Listeria monocytogenes

Listeria monocytogenes (Lm) is a bacterial pathogen that infects the brain via parasitized monocytes. CCR2 is important for monocyte migration into the brain after it is infected, but the degree of CCR2 involvement in monocyte migration to the CNS during systemic infection is less clear. Our recent data demonstrate that systemic infection with non-neuroinvasive ΔactA Lm mutants triggers IFN-γ-dependent brain influxes of Ly-6Chigh monocytes. Studies presented here tested the extent to which CCR2 and IFN-γ are essential for monocyte migration to the brain during systemic infection with virulent Lm. For this, we assessed expression of monocyte-attracting chemokines in brains of normal and IFN-γ mice during infection and tested the degree to which brain influxes of Ly-6Chigh monocytes were inhibited in chemokine- and chemokine receptor-deficient mice. In normal mice, systemic infection induced up-regulation of CCR2-binding (CCL2, CCL7, CCL8, CCL12) and CXCR3-binding chemokines (CXCL9, CXCL10). IFN-γ mice had negligible mRNA and protein expression of CXCR3-binding chemokines, whereas expression of CCR2-binding chemokines was reduced, but remained significant. In addition, infection-triggered monocyte influxes were significantly reduced in IFN-γ mice. Remarkably, brain monocyte influxes were normal during infection of CXCR3-, CCL2-, CCR1-, CCR5-, and CX3CR1-deficient mice. Influxes were transiently reduced in CCR2−/− mice, corresponding with retention of monocytes in the bone marrow but this was eventually overcome during infection. These data show that IFN-γ is critical for triggering brain influxes of Ly-6Chigh monocytes during systemic infection with virulent Lm. This initial burst of monocyte migration is largely independent of individual chemokine receptors.