Murine Granulocyte-Macrophage and Mast Cell Colony Formation Promoted by Nerve Growth Factor

Abstract

The nerve growth factor (NGF) is widely distributed in the target tissues of sympathetic neurons. Hemopoietic organs such as the bone marrow (BM) and spleens are known to be innervated by noradrenergic sympathetic neurons. Some of their constitutive cells express NGF receptors (lymphocytes and stroma cells) and its biologic effects have been extensively studied in the immune system and inflammatory responses. However, the effects of NGF on hemopoiesis have been little examined. Recently, we demonstrated that NGF promoted mast cell colony formation from murine BM cells (BMC) or BMC-derived cultured mast cells and induced the phenotypic changes in standard hemopoietic assays. Besides, we demonstrated NGF-enhanced murine neutrophil survival and functional properties. In this study, in order to investigate NGF activities on neutrophil differentiation, we examined granulocyte-macrophage (GM) colony formation from murine BMC or spleen cells (SC) in the methylcellulose culture. We also assessed mast cell colony formation. GM colonies were counted on day 5 and mast cell colonies were counted on day 20 in culture. Although NGF alone (50 ng/ml) neither supported GM nor mast cell colony formation, addition of various doses of NGF to the suboptimal dose of pokeweed mitogen-stimulated SC-conditioned medium (2.5%) or interleukin 3 (50 U/ml), well-known colony-stimulating factors, increased the number of GM and mast cell colonies from both BMC and SC in a dose-dependent manner. These colony formation-enhancing effects of NGF were inhibited by the addition of neutralizing sheep anti-NGF antibodies. The results suggest that NGF may act to develop granulopoiesis including neutrophil and mast cell differentiation in cooperation with hemopoietic factor(s) during inflammatory processes.

Neurotrophins Regulate Bone Marrow Stromal Cell IL-6 Expression through the MAPK Pathway.

“…NGF has been demonstrated as an important factor for hematopoietic colony growth and differentiation [41]. Previous work documents its ability to directly influence proliferation, differentiation, and maturation of myeloid progenitors along with induction of migration, survival and activation of mature hematopoietic cells [42][43][44]. NGF is also a chemotactic stimulus for human leukocytes and macrophages [45,46].…”

“…As such, neurotrophins are positioned to regulate the availability of inflammatory cells derived from the marrow, through both direct [41][42][43][44] and indirect mechanisms. Taken together, our data suggest a central role for neurotrophins in the inflammatory process subsequent to infection and identify bone marrow stroma as a novel target for these factors.…”

Nerve Growth Factor Activates Mast Cells Through the Collaborative Interaction with Lysophosphatidylserine Expressed on the Membrane Surface of Activated Platelets

“…In addition to neurotrophic activity, increasing evidences give rise to possible multifunctional properties of NGF on immunocompetent cells including lymphocytes, monocytes/macrophages, and mast cells through functional NGF receptors (4 -11). In prior studies, we have demonstrated that NGF promotes not only granulocyte differentiation from human PBMC and murine bone marrow cells (12,13), but also differentiation of connective tissue-type mast cells from murine bone marrow cells and bone marrow-derived culture mast cells (14). NGF is capable of supporting survival of neutrophils (15), eosinophils (16), and mast cells (9) by preventing apoptosis, and enhancing functional properties of neutrophils, eosinophils, macrophages, and mast cells: phagocytosis, superoxide production, matrix metalloproteinase-9 production, and chemotaxis (11, 12, 16 -20).…”

The expanding role of nerve growth factor: from neurotrophic activity to immunologic diseases

“…NGF acts as a colony-stimulating factor for human and murine myeloid progenitor cells (83,84). It affects specifically basophilic differentiation (85); induces mediator release from basophils, eosinophils, and neutrophils (80,86,87); acts as a chemoattractant for polytnorphonuclear leukocytes (88,89); and enhances neutrophil phagocytosis (80).…”