STAT1 deficiency unexpectedly and markedly exacerbates the pathophysiological actions of IFN-alpha in the central nervous system.

Abstract

Although signal transducer and activator of transcription 1 (STAT1) is an essential signaling molecule in many IFN-alpha-regulated processes, some biological responses to IFN-alpha can occur independently of STAT1. To establish the role of STAT1 in mediating the biological actions of IFN-alpha in the CNS, transgenic mice [termed glial fibrillary acidic protein (GFAP)-IFN-alpha] with astrocyte production of IFN-alpha were bred to be null for the STAT1 gene. Surprisingly, GFAP-IFN-alpha mice deficient for STAT1 developed earlier onset and more severe neurological disease with increased lethality compared with GFAP-IFN-alpha mice sufficient for STAT1. Whereas the brain of 2- to 3-month-old GFAP-IFN-alpha mice showed little, if any abnormality, the brain from GFAP-IFN-alpha mice deficient for STAT1 had severe neurodegeneration, inflammation, calcification with increased apoptosis, and glial activation. However, the cerebral expression of a number of IFN-regulated STAT1-dependent genes increased in GFAP-IFN-alpha mice but was reduced markedly in GFAP-IFN-alpha STAT1-null mice. Of many other signaling molecules examined, STAT3 alone was activated significantly in the brain of GFAP-IFN-alpha STAT1-null mice. Thus, in the absence of STAT1, alternative signaling pathways mediate pathophysiological actions of IFN-alpha in the living brain, giving rise to severe encephalopathy. Finally, STAT1 or a downstream component of the JAKSTAT pathway may protect against such IFN-alpha-mediated injury in the CNS.