The cell-specific induction of CXCL9 by interferon (IFN)-γ in CNS microglia is determined by the myeloid transcription factor PU.1 (51.6)

Abstract

The IFN-γ-inducible chemokines CXCL9 and CXCL10 bind to CXCR3 and are implicated in the pathogenesis of T-cell-mediated immunity in the CNS. However, the cellular localization of these chemokines differs with CXCL9 produced by macrophage/microglia (M/M) while CXCL10 is produced by both M/M and astrocytes. Here we determined the mechanism for the M/M-restricted expression of the Cxcl9 gene induced by IFN-γ. Of a number of transcription factors involved with IFN-γ-mediated gene regulation, PU.1 was present constitutively in murine M/M but not in astrocytes. Both in the brain and in culture, PU.1 was localized exclusively to the nucleus of M/M cells. ChIP analysis revealed that STAT-1, PU.1 and IRF8 were bound to the CXCL9 promoter in IFN-γ-treated M/M, whereas in astrocytes STAT-1 alone bound to the CXCL9 promoter. STAT-1 but not IRF8 was critical for IFN-γ-induced expression of both the Cxcl9 and Cxcl10 genes in M/M and in M/M and astrocytes, respectively. The siRNA-mediated knockdown of PU.1 in M/M markedly impaired IFN-γ induced CXCL9 but not STAT1 or IRF8. D1A astrocyte cells showed partial reprogramming to a myeloid phenotype after transduction with PU.1 with expression of CD11b and acquisition of IFN-γ-induced CXCL9. Thus, while IFN-γ is a pivotal mediator of both Cxcl9 and Cxcl10 gene expression, this cytokine differentially induces the expression of CXCL9 in myeloid cells through a mechanism that is determined by PU.1. Support: NIH NS044905.