The Impact of Integrin ?2 on Granulocyte/Macrophage Progenitor Proliferation.

ABSTRACT: Previously, we reported that although the HSPC frequency in bone marrow cells (BMC) was comparable between ?2-/- and ?2+/+ mice, transplantation of ?2-/- BMC into lethally irradiated CD45.1 recipient resulted in more myeloid cell production than ?2+/+ BMC. The objective of this study is to address if integrin ?2 deficiency skews granulocyte/macrophage progenitor (GMP) proliferation. FACS analysis demonstrated that GMP frequency and cell number were higher and megakaryocyte/erythrocyte progenitor frequency and cell number were lower in ?2-/- mice than ?2+/+ mice. However, the common myeloid progenitors (CMP) frequency and cell number were similar between the two groups. The increased GMP number was due to GMP proliferation as evidenced by the percentage of BrdU-incorporating GMP. Whole genome transcriptome analysis identified increased Fc?RI? expression in ?2-/- CMP compared to ?2+/+ CMP. Fc?RI? expression on ?2-/- GMP was detected increased in ?2-/- mice by qRT-PCR and FACS. Although transplantation of Fc?RI?^hi GMP or Fc?RI?^lo GMP into lethally irradiated CD45.1 recipient resulted in comparable myeloid cell production, transplantation of ?2 deficient Fc?RI?^hi GMP generated more myeloid cells than ?2+/+ Fc?RI?^hi GMP. GATA2 expression was increased in ?2-/- GMP. Using a luciferase reporter assay, we demonstrated that mutation of the GATA2 binding site in the Fc?RI? promoter region diminished Fc?RI? transcription. In vitro, the addition of IgE, the ligand of Fc?RI?, promoted GMP expansion, which was abrogated by inhibition of JNK phosphorylation. Integrin ?2 deficiency promoted GMP proliferation and myeloid cell production, which was mediated via Fc?RI?/IgE-induced JNK phosphorylation in GMP. Stem Cells 2019;37:430-440.

SUBMITTER: Zhang LJ 

PROVIDER: S-EPMC6849781 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature