Interleukin-33 signaling controls the development of iron-recycling macrophages

Lu, Yuning; Basatemur, Gemma; Scott, Ian C.; Chiarugi, Davide; Clement, Marc; Harrison, James; Jugdaohsingh, Ravin; Yu, Xian; Newland, Stephen A.; Jolin, Helen E.; Li, Xuan; Chen, Xiao; Szymanska, Monika; Haraldsen, Guttorm; Palmer, Gaby; Fallon, Padraic G.; Cohen, E. Suzanne; McKenzie, Andrew N.J.; Mallat, Ziad

doi:10.1016/j.immuni.2020.03.006

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Interleukin-33 signaling controls the development of iron-recycling macrophages

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Chiarugi, Davide
Methods and Development Group Computing and Databases Services, MPI for Human Cognitive and Brain Sciences, Max Planck Society;

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Lu, Y., Basatemur, G., Scott, I. C., Chiarugi, D., Clement, M., Harrison, J., et al. (2020). Interleukin-33 signaling controls the development of iron-recycling macrophages. Immunity, 52(5), 782-793.e5. doi:10.1016/j.immuni.2020.03.006.

Cite as: https://hdl.handle.net/21.11116/0000-000A-F724-7

Abstract

Splenic red pulp macrophages (RPMs) contribute to erythrocyte homeostasis and are required for iron recycling. Heme induces the expression of SPIC transcription factor in monocyte-derived macrophages and promotes their differentiation into RPM precursors, pre-RPMs. However, the requirements for differentiation into mature RPMs remain unknown. Here, we have demonstrated that interleukin (IL)-33 associated with erythrocytes and co-cooperated with heme to promote the generation of mature RPMs through activation of the MyD88 adaptor protein and ERK1/2 kinases downstream of the IL-33 receptor, IL1RL1. IL-33- and IL1RL1-deficient mice showed defective iron recycling and increased splenic iron deposition. Gene expression and chromatin accessibility studies revealed a role for GATA transcription factors downstream of IL-33 signaling during the development of pre-RPMs that retained full potential to differentiate into RPMs. Thus, IL-33 instructs the development of RPMs as a response to physiological erythrocyte damage with important implications to iron recycling and iron homeostasis.