Map4k4

Neutrophils are specialized innate cells that require constant replenishment from proliferative bone marrow (BM) precursors as a result of their short half-life. Although it is established that neutrophils are derived from the granulocyte-macrophage progenitor (GMP), the differentiation pathways from GMP to functional mature neutrophils are poorly defined. Using a PU-learning-based supervised machine learning method incorporating data from static to dynamic, physiological to pathological, we predicted that Mitogen-Activated Protein Kinase4 (MAP4K4) might be an important intrinsic modulator for neutrophil development, and homeostasis. Map4k4-deficient mice display neutropenic phenotypes in the periphery. The in vivo and in vitro studies showed that Map4k4 deficiency mainly impaired the developing process of myeloid progenitors to neutrophils in an intrinsic manner. Mechanism studies showed that transcription factors and apoptosis pathways mediated the impaired development of neutrophils caused by Map4k4 deficiency. Thus, our findings identify a previously unrecognized function of Map4k4 as a cell type-specific positive regulator of neutrophil generation and homeostasis. Figure 1. Machine learning piepeline.