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Interleukin-33 Signaling Controls the Development of Iron-Recycling Macrophages.

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Basatemur, Gemma 
Scott, Ian C 
Chiarugi, Davide 
Clement, Marc 


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.



erythrophagocytosis, interleukin-33, interleukin-33 receptor, interleukins, iron metabolism, red pulp macrophage, Animals, Erythrocytes, Heme, Homeostasis, Interleukin-1 Receptor-Like 1 Protein, Interleukin-33, Iron, Macrophages, Mice, Knockout, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Myeloid Differentiation Factor 88, Signal Transduction, Spleen

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Elsevier BV
British Heart Foundation (CH/10/001/27642)
British Heart Foundation (RG/15/11/31593)
British Heart Foundation (PG/17/9/32834)
Medical Research Council (MR/R005699/1)