Mycobacteria‐induced granuloma necrosis depends on IRF‐1

In a mouse model of mycobacteria‐induced immunopathology, wild‐type C57BL/6 (WT), IL‐18‐knockout (KO) and IFN‐αβ 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 and IRF‐1‐KO mice identified a set of genes whose differential regulation was closely associated with granuloma necrosis, among them cathepsin K, cystatin F and matrix metalloprotease 10. Further microarray‐based comparison of gene expression 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 I 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.