IRF5 in defining inflammatory macrophages: studies in vitro and in vivo

Macrophages are an integral part of the innate immune system and key players in pathogen clearance and tissue remodelling. Both functions are accomplished by a heterogeneous network of diverse macrophage populations that display pro- and anti-inflammatory properties. Understanding the molecular pathways that control this heterogeneity should provide abundant scope for the generation of more specific and effective therapeutics. Previously, our laboratory identified the transcription factor interferon regulatory factor 5 (IRF5) as the master regulator of the pro-inflammatory phenotype in human in vitro differentiated macrophages. Here, we show that murine macrophages with pro-inflammatory capacities in vitro and in vivo are also characterised by high levels of IRF5. IRF5 is upregulated in vitro in response to inflammatory stimuli such as GM-CSF and IFN-γ and in a subset of in vivo macrophages in the arthritic knee joint during the model of antigen-induced arthritis (AIA). IRF5 is also expressed in other myeloid cells in vivo, especially in Ly6Chi monocytes and to a lesser extent in dendritic cells and neutrophils. We furthermore explored the role of IRF5 and IRF5-expressing macrophages in acute inflammation using two different models, AIA and acute lung injury, which are characterised by an extensive initial influx of neutrophils. Mice lacking IRF5 display reduced disease severity and decreased signs of inflammation in both models. Specifically, far fewer neutrophils accumulate at the site of inflammation. We investigated the molecular mechanisms underlying this phenomenon and discovered that IRF5-/- mice produced reduced levels of chemokines important for neutrophil recruitment, such as CXCL1. These studies extend our knowledge of the IRF5 expression pattern in vivo and suggest that in addition to the previously proposed role of IRF5 in chronic inflammation, it also has an important function in orchestrating initial acute responses. Thus, IRF5 blockade may be beneficial for both acute and chronic inflammation.