Deletion of Tristetraprolin Caused Spontaneous Reactive Granulopoiesis by a Non–Cell-Autonomous Mechanism Without Disturbing Long-Term Hematopoietic Stem Cell Quiescence

Abstract

Tristetraprolin (TTP, Zfp36, Nup475, Tis11) dramatically reduces the stability of target mRNAs by binding to AU-rich elements in their 3' untranslated regions. Through this mechanism, TTP functions as a rheostatic, temporal regulator of gene expression. TTP knockout (KO) mice exhibit completely penetrant granulocytic hyperplasia. We have shown that the hematopoietic stem-progenitor cell compartment in TTP KO mice is also altered. Although no change was detected in long-term hematopoietic stem cell (HSC) frequency or function, as assayed by immunophenotypic markers or limiting dilution transplants, we observed increases in the frequencies and numbers of short-term HSCs, multipotent progenitors, and granulocyte-monocyte progenitors. This pattern is consistent with "reactive granulopoiesis," in which committed myeloid progenitors and more primitive progenitors cycle more actively to increase production of mature granulocytes in response to infection or adjuvant. We created reverse chimeras by transplanting wild-type bone marrow into TTP KO mice and found the "reactive granulopoiesis" phenocopied, indicating a non-hematopoietic stem-progenitor cell-autonomous mechanism. Correspondingly, we found elevated levels of the granulopoietic TTP targets IL-1β, TNF-α, and IL-6 in the plasma of TTP KO mice. Consistent with the non-cell-autonomous nature of the phenotype, we found elevated levels of IL-1β, TNF-α, and IL-6 transcripts in the livers of TTP KO mice and no detectable difference in the bone marrows. These findings demonstrate the importance of TTP in inflammatory homeostasis and highlight the ability of the hematopoietic system to respond to stress without significant numbers of quiescent HSCs entering the cell cycle.