24: Interferon regulatory factor 4 and inflammation

Abstract

Interferon regulatory factor 4 (IRF4) was initially thought to be expressed only in cells of the lymphoid lineage, with IRF4 deficient (IRF4−/−) mice having increased numbers of immature T and B cells with impaired functions. More recently IRF4 has also been found to be expressed in myeloid cells. However, its function in macrophage development and regulation is not clear. It has been reported to be required for the generation of both the pro-inflammatory M1 and the anti-inflammatory M2 macrophage subpopulations. In the current study we have found that the expression of IRF4 was higher in the pro-inflammatory granulocyte macrophage-colony stimulating factor (GM-CSF)-induced bone marrow-derived macrophages than in the macrophage-colony stimulating factor (M-CSF)-induced bone marrow-derived macrophages. We therefore hypothesised that IRF4 would be required for the regulation of pro-inflammatory genes and its deficiency would prevent mice from developing inflammatory responses. Unexpectedly, when the KRN serum-transfer arthritis model, which does not require T or B cells, was induced in wild type (WT) and IRF4−/− mice, the latter showed a more severe disease phenotype. Significantly larger spleens were seen in the IRF4−/− mice compared with the WT, comprising of more Ly6Clo monocytes. IRF4−/− mice also had more macrophages than WT mice. RNA analysis of myeloperoxidase suggests that IRF4−/− may have elevated numbers of neutrophils in the joints. Given these unexpected findings, experiments are currently being performed to further investigate the underlying functions of IRF4 in inflammation.