Mycobacteria-induced granuloma necrosis depends on IRF-1

In a mouse model of mycobacteria-induced immunopathology, wildtype C57BL/6 (WT) and IFNαβ-receptor-KO mice developed circumscript, centrally necrotizing granulomatous lesions in response to aerosol infection with M. avium, whereas mice deficient in the IFN-γ-receptor, STAT-1 or IRF-1 did not exhibit granuloma necrosis. Comparative, microarray-based gene expression analysis in the lungs of infected WT, IFN-γ-KO and IRF-1-KO mice revealed four distinct clusters of genes with variable dependence on the presence of IFN-γ, IRF-1 or both. In particular, IRF-1 appeared to be directly involved in the differentiation of a type 1 immune response to mycobacterial infection. In summary, IRF-1, rather than being a mere transcription factor downstream of IFN-γ, may be a master regulator of mycobacteria-induced immunopathology.