Advertisement

Trib1 regulates eosinophil lineage commitment and identity by restraining the neutrophil program

Ethan A Mack, Sarah J Stein, Kelly S Rome, Lanwei Xu, Gerald B Wertheim, Rossana CN Melo and Warren S Pear

Key Points

  • Trib1 controls both eosinophil lineage commitment and identity.

  • Trib1 integrates IL-5 and C/EBPα signals to promote eosinophil lineage fidelity by suppressing the neutrophil program.

Abstract

Eosinophils and neutrophils are critical for host defense, yet gaps in understanding how granulocytes differentiate from HSCs into mature effectors remain. The pseudokinase Trib1 is an important regulator of granulocytes; knockout mice lack eosinophils and have increased neutrophils. However, how Trib1 regulates cellular identity and function during eosinophilopoiesis is not understood. Trib1 expression markedly increases with eosinophil-lineage commitment in eosinophil progenitors (EoPs), downstream of the GMP. Using hematopoietic- and eosinophil-lineage-specific Trib1 deletion, we found that Trib1 regulates both granulocyte precursor lineage commitment and mature eosinophil identity. Conditional Trib1 deletion in HSCs reduced the size of the EoP pool and increased neutrophils, whereas deletion following eosinophil lineage commitment blunted the decrease in EoPs without increasing neutrophils. In both modes of deletion, Trib1-deficient mice expanded a stable population of Ly6G+ eosinophils with neutrophilic characteristics and functions, and had increased C/EBPα p42. Using an ex vivo differentiation assay, we found that IL-5 supports the generation of Ly6G+ eosinophils from Trib1-deficient cells, but is not sufficient to restore normal eosinophil differentiation and development. Furthermore, we demonstrated that Trib1 loss blunted eosinophil migration and altered chemokine receptor expression, both in vivo and ex vivo. Finally, we showed that Trib1 controls eosinophil identity by modulating C/EBPα. Together, our findings provide new insights into early events in myelopoiesis, whereby Trib1 functions at two distinct stages to guide eosinophil lineage commitment from the GMP and suppress the neutrophil program, promoting eosinophil terminal identity and maintaining lineage fidelity.

  • Submitted September 18, 2018.
  • Revision received March 18, 2019.
  • Accepted March 26, 2019.