Tribbles Homologue 1 Controls Granulocyte Progenitor Commitment And Terminal Cell Identity And Function

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Doctor of Philosophy (PhD)
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Allergy and Immunology
Immunology and Infectious Disease
Medical Immunology
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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 during eosinophilopoiesis and cellular function of mature eosinophils and neutrophils 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 that retained neutrophilic characteristics and functions, and had increased C/EBPα p42. Using an ex vivo differentiation assay, we identified a previously uncharacterized role for IL-5 in supporting both eosinophil and neutrophil production from the GMP; Trib1 suppressed the neutrophil gene program in lineage-committed eosinophil precursors in response to IL-5 signaling. Furthermore, we demonstrated that Trib1 loss blunted eosinophil migration and altered chemokine receptor expression, both in vivo and ex vivo. We showed that Trib1 controls eosinophil identity by modulating C/EBPα. Trib1 also controls neutrophil inflammatory function by modulating activation of the AKT, MAPK, and NF-κB pathways Together, our findings provide new insights into early events in myelopoiesis, whereby Trib1 functions at multiple distinct stages. Trib1 guides eosinophil lineage commitment from the GMP, suppresses the neutrophil program, and limits neutrophil inflammatory function, together promoting granulocyte terminal identity, lineage fidelity, and homeostasis.

Warren S. Pear
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