Molecular Biology Of Mast Cell Growth And Differentiation

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Abstract

The biologic potential of mast cells is shown by a number of recent observations. First, we have found that human mast cells have the ability to synthesize and release serotonin (5-HT). Further, mast cells and mast cell progenitors will chemotax to 5-HT both in vitro and in vivo by interacting with the 5-HT1A mast cell receptor. These observations point to a here-to-fore unrecognized set of interactions between mast cells and 5-HT. Clinically this may help explain why some antihistamines with antiserotonergic properties have found preferential use in the treatment of some forms of urticaria.[unreadable] [unreadable] Second, inhalation of crystalline silica results in pulmonary fibrosis and silicosis. It has been suggested that mast cells play a role in these conditions. How mast cells would influence pathology is unknown. We thus explored mast cell interactions with silica in vitro and in B6.Cg-KitW-sh mast cell deficient mice. B6.Cg-KitW-sh mice did not develop inflammation or significant collagen deposition following instillation of silica, while C57Bl6 wild-type mice did have these findings. We then examined the ability of silica to activate mouse bone marrow derived mast cells, including degranulation, production of reactive oxygen species and inflammatory mediators; and the effects of silica on FcepsilonRI-dependent activation. Silica did not induce mast cell degranulation. However, TNF-alpha, IL-13 and MCP-1; protease activity, and production of ROS were dose dependently increased following silica exposure; and production was enhanced following FcepsilonRI stimulation. As silica mediates some effects in macrophages through scavenger receptors, we first determined that mast cells expressed scavenger receptors; then explored the involvement of SR-A and MARCO. Silica-induced ROS formation, apoptosis and TNF-alpha production were reduced in BMMC obtained from SR-A, MARCO and SR-AMARCO KO mice. These findings demonstrate that silica directs mast cell production of inflammatory mediators, in part through scavenger receptors.[unreadable] [unreadable] We have also proposed that unlike other HIV-vulnerable cell lineages, progenitor mast cells (prMCs), cultured in vitro from undifferentiated bone marrow-derived CD34 pluripotent precursors, are susceptible to infection during a limited period of their ontogeny. As infected prMCs mature in culture, they lose expression of viral chemokine co-receptors necessary for viral entry and develop into long-lived, latently infected mature tissue mast cells, resistant to new infection. In vivo recruitment of prMCs to different tissue compartments occurs normally, thus possibly allowing populations of circulating and potentially HIV-susceptible prMCs to spread persistent infection to diverse tissue compartments. We found exidence to this effect by demonstrating that HIV-infected women have both circulating prMCs and placental tissue MCs that harbor inducible infectious HIV. Furthermore, infectious virus, capable of infecting allo-activated fetal cord blood mononuclear cells, could be induced in isolated latently-infected PLMCs after weeks in culture in vitro. [unreadable] [unreadable] Finally, we examined the effect of ionizing gamma-radiation on mast cells. Gamma-radiation has several therapeutic indications including bone marrow transplantation and tumor ablation. Among immune cells, susceptibility of lymphocytes to gamma-radiation is well known. However, there was little information on the effects of gamma-radiation on mast cells. We thus examined both human and murine mast cell survival and activation, including mechanisms related to innate and acquired immune responses following gamma-irradiation. Data revealed that human and murine mast cells were resistant to gamma-radiation-induced cytotoxicity and that irradiation did not directly induce mast cell degranulation. Instead, a transient attenuation of IgE-mediated beta-hexosaminidase release and cytokine production was observed. Mast cells retained the ability to phagocytose E. coli particles and respond to TLR ligands. In vivo, there was no decrease in mast cell numbers in skin of irradiated mice. Additionally, mast cells retained the ability to respond to antigen in vivo. Mast cells are thus resistant to the cytotoxic effects and alterations in function induced by gamma-radiation; and are able to respond to both innate and acquired immune activation signals following exposure to gamma-radiation.