Spi-C Negatively Regulates Murine Eosinophil Differentiation

Abstract

Eosinophils are bone marrow-derived granulocytes that normally comprise less than 5% of leukocytes in the blood, but can be found in higher numbers in tissues such as the bone marrow and gastrointestinal tract. Eosinophilia is associated with numerous clinical disorders including atopic diseases, parasitic infections, hypereosinophilic syndrome, and cancer. Expression of Spi-C was originally reported to be limited to B cell and macrophage lineages, but we have reported that upregulation of Spi-C expression within the lung was dependent on the presence of eosinophils in an experimental chronic asthma model. In this study we investigated the role of Spi-C during eosinophil differentiation. At baseline, we observed increased numbers of bone marrow and splenic eosinophils in Spi-C-deficient (Spi-CKO) mice. Stimulation of low-density bone marrow (LDBM) cells with the eosinophil-promoting cytokine IL-5 resulted in 100-fold increase in Spi-C mRNA expression. Cultured Spi-CKO LDBM cells had an accelerated rate of eosinophil progenitor (EoP) differentiation which yielded higher numbers of eosinophils with increased effector functions, including enhanced chemotaxis, granule protein production and release compared to wild-type mice. In addition, induction of asthma resulted in amplified airway eosinophilia in Spi-CKO mice compared to wild-type controls. Together our data indicate that Spi-C negatively regulates eosinophil differentiation during homeostasis and disease. Defining the molecular regulators of eosinophil differentiation and function will undoubtedly provide key information with clinical applications. Disclosures:Rothenberg:Teva Pharmaceutical: Consultancy, Ownership Interest receiving Other; Immune Pharmaceutical: Consultancy, Membership on an entity's Board of Directors or advisory committees, Ownership Interest receiving, Ownership Interest receiving Other.