Cell-Intrinsic Regulation of Cytokine Responses by I-mfa Controls Eosinophil Development

Abstract

Abstract The response of hematopoietic stem and progenitor cells to cytokines and other signals in the bone marrow (BM) niche is regulated by a complex network of cell-intrinsic factors that is still not well understood. We have identified a small cysteine-rich protein, the Inhibitor of MyoD Family A (I-mfa), as a novel regulator of hematopoiesis and lineage development. I-mfa is known to regulate β-catenin signaling, a pathway that is activated by the IL-3-family of cytokines (IL-3, IL-5, GM-CSF) which are important during myeloid lineage differentiation. We therefore hypothesized that I-mfa would influence the production of myeloid progenitors and mature cells by regulating the response to these cytokines. To test this, we compared the BM and spleens of wild-type (WT) and I-mfa-knockout (KO) mice by flow cytometry. I-mfa KO animals had expanded common myeloid progenitor and granulocyte/macrophage progenitor populations compared to WT, and showed eosinophilia in the spleen. The function of the BM was analyzed by myeloid colony forming unit (CFU-M) assays, showing significantly higher granulocyte colony output from I-mfa KO BM compared to WT. Mechanistically, myeloid progenitor cell lines over-expressing I-mfa were resistant to β-catenin activation in response to cytokine and Wnt ligand stimulation. These data taken together suggest that I-mfa is a novel regulator of eosinophil development through its regulation of β-catenin signaling downstream of cytokine receptors. These results present a new insight into disease states mediated by eosinophilia such as allergic asthma and may mechanistically underscore eosinophilia during the progression of myeloid leukemias.