IFN-gamma 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 DeltaactA Lm mutants triggers IFN-gamma-dependent brain influxes of Ly-6C(high) monocytes. Studies presented here tested the extent to which CCR2 and IFN-gamma 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-gamma mice during infection and tested the degree to which brain influxes of Ly-6C(high) 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-gamma 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-gamma 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-gamma is critical for triggering brain influxes of Ly-6C(high) monocytes during systemic infection with virulent Lm. This initial burst of monocyte migration is largely independent of individual chemokine receptors.
Drevets
Douglas A
DA
Department of Medicine, Oklahoma University Health Sciences Center, Oklahoma City, OK, USA. douglas-drevets@ouhsc.edu
Dillon
Marilyn J
MJ
Schawang
Jennifer E
JE
Stoner
Julie A
JA
Leenen
Pieter J M
PJ
D000818:Animals; D001921:Brain / Q000473:pathology*; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000494:pharmacology*; D008088:Listeriosis / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects* / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D054390:Receptors, CCR2 / Q000187:drug effects* / Q000235:genetics; D019707:Receptors, Chemokine / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D007371:Interferon-gamma