The type I interferon-alpha mediates a more severe neurological disease in the absence of the canonical signaling molecule interferon regulatory factor 9.

Type I interferons (IFN) are crucial in host defense but also are implicated as causative factors for neurological disease. Interferon regulatory factor (IRF9) is involved in type I IFN-regulated gene expression where it associates with STAT1:STAT2 heterodimers to form the transcriptional complex ISGF3. The role of IRF9 in cellular responses to type I IFN is poorly defined in vivo and hence was examined here. While transgenic mice (termed GIFN) with chronic production of low levels of IFN-alpha in the CNS were relatively unaffected, the same animals lacking IRF9 [GIFNxIRF9 knock-out (KO)] had cataracts, became moribund, and died prematurely. The brain of GIFNxIRF9 KO mice showed calcification with pronounced inflammation and neurodegeneration whereas inflammation and retinal degeneration affected the eyes. In addition, IFN-gamma-like gene expression in the CNS in association with IFN-gamma mRNA and increased phosphotyrosine-STAT1 suggested a role for IFN-gamma. However, GIFNxIRF9 KO mice deficient for IFN-gamma signaling developed an even more severe and accelerated disease, indicating that IFN-gamma was protective. In IRF9-deficient cultured mixed glial cells, IFN-alpha induced prolonged activation of STAT1 and STAT2 and induced the expression of IFN-gamma-like genes. We conclude that (1) type I IFN signaling and cellular responses can occur in vivo in the absence of IRF9, (2) IRF9 protects against the pathophysiological actions of type I IFN in the CNS, and (3) STAT1 and possibly STAT2 participate in alternative IRF9-independent signaling pathways activated by IFN-alpha in glial cells resulting in enhanced IFN-gamma-like responses.