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

Summary

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.

Graphical Abstract

Highlights

• •

  IL-33 signaling promotes development of monocyte-derived red pulp macrophages (RPMs)

• •

  Il33 ^−/− and Il1rl1 ^−/− mice have decreased RPMs and splenic erythrophagocytosis

• •

  ERK activation is required for RPM development and is potentiated by hemin and IL-33

• •

  GATA2 instructs RPM development and is aberrant in Il1rl1 ^−/− RPM precursors

Abstract

Splenic red pulp macrophages (RPMs) are critical for iron recycling. Here, Lu et al. implicate a role for IL-33 signaling in the regulation of GATA2, which controls the transition of monocytes to produce pre-RPMs that are competent to terminally differentiate into mature RPMs.