IRF5 controls both acute and chronic inflammation.
Whereas the importance of macrophages in chronic inflammatory diseases is well recognized, there is an increasing awareness that neutrophils may also play an important role. In addition to the well-documented heterogeneity of macrophage phenotypes and functions, neutrophils also show remarkable phenotypic diversity among tissues. Understanding the molecular pathways that control this heterogeneity should provide abundant scope for the generation of more specific and effective therapeutics. We have shown that the transcription factor IFN regulatory factor 5 (IRF5) polarizes macrophages toward an inflammatory phenotype. IRF5 is also expressed in other myeloid cells, including neutrophils, where it was linked to neutrophil function. In this study we explored the role of IRF5 in models of acute inflammation, including antigen-induced inflammatory arthritis and lung injury, both involving an extensive influx of neutrophils. Mice lacking IRF5 accumulate far fewer neutrophils at the site of inflammation due to the reduced levels of chemokines important for neutrophil recruitment, such as the chemokine (C-X-C motif) ligand 1. Furthermore we found that neutrophils express little IRF5 in the joints and that their migratory properties are not affected by the IRF5 deficiency. These studies extend prior ones suggesting that inhibiting IRF5 might be useful for chronic macrophage-induced inflammation and suggest that IRF5 blockade would ameliorate more acute forms of inflammation, including lung injury.
Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, United Kingdom;
Miriam
M
Weiss
Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, United Kingdom; National Heart and Lung Institute, Imperial College, London SW7 2AZ, United Kingdom.
Adam J
AJ
Byrne
Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, United Kingdom;
Katrina
K
Blazek
Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, United Kingdom;
David G
DG
Saliba
National Heart and Lung Institute, Imperial College, London SW7 2AZ, United Kingdom.
James E
JE
Pease
Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, United Kingdom;
Dany
D
Perocheau
Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, United Kingdom; irina.udalova@kennedy.ox.ac.uk marc.feldmann@kennedy.ox.ac.uk.
Marc
M
Feldmann
Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, United Kingdom; irina.udalova@kennedy.ox.ac.uk marc.feldmann@kennedy.ox.ac.uk.
Irina A
IA
Udalova
D000208:Acute Disease; D000818:Animals; D018925:Chemokines / Q000502:physiology; D002908:Chronic Disease; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology*; D050835:Interferon Regulatory Factors / Q000502:physiology*; D008264:Macrophages / Q000473:pathology; D051379:Mice; D013583:Synovial Membrane / Q000473:pathology
D018925:Chemokines; D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse
IRF5; acute inflammation; arthritis; macrophages; neutrophils