G-CSF induced neutrophil invasion of the CNS is inhibited by Interferon γ (VIR9P.1150)

Abstract

Abstract Inflammation of the brainstem (BS) of wildtype (wt) 129 mice due to uncontrolled invasion by Ly6Chigh inflammatory monocytes (IM) and neutrophils is causally implicated in fatal HSV induced encephalitis (HSE). Anti-viral treatment with acyclovir following virus entry into BS cannot protect mice, as inflammation continues unabated. We showed previously that IL-10 regulates IM infiltration into BS. We determined the role of IFNγ, a key pleiotropic cytokine that directs the host immune response by inducing potent inflammatory or regulatory activities, in HSE. IFNγ knockout (GKO) mice developed HSE much quicker than wt or Rag mice. Surprisingly, mortality did not correlate with the ability to control virus replication but rather with massive expansion and infiltration of neutrophils into the BS. Neutrophil expansion in the absence of IFNγ was not due to increased IL-17 but rather to augmented secretion of G-CSF especially in CNS. Depletion of G-CSF by administration of anti G-CSF Ab or 25 mg IVIG (high dose), which contains anti G-CSF Ab, but not 4 mg (low dose) inhibited progenitor proliferation and neutrophil output from bone marrow and protected GKO mice. Importantly, reduction of serum G-CSF levels resulted in renewed IL-10 secretion by ICOS+ CD4 T cells and Tregs, which limited IM expansion. This study reveals that the complex interplay of IFNγ with G-CSF and IL-10 determines the ability to skew neutrophil or monocyte output from the bone marrow in response to infection.