Development, migration, and survival of mast cells

Abstract

Mast cells play a pivotal role in immediate hypersensitivity and chronic allergic reactions that can contribute to asthma, atopic dermatitis, and other allergic diseases. Because mast cell numbers are increased at sites of inflammation in allergic diseases, pharmacologic intervention into the proliferation, migration, and survival (or apoptosis) of mast cells could be a promising strategy for the management of allergic diseases. Mast cells differentiate from multipotent hematopoietic progenitors in the bone marrow. Stem cell factor (SCF) is a major chemotactic factor for mast cells and their progenitors. SCF also elicits cell-cell and cell-substratum adhesion, facilitates the proliferation, and sustains the survival, differentiation, and maturation, of mast cells. Therefore, many aspects of mast cell biology can be understood as interactions of mast cells and their precursors with SCF and factors that modulate their responses to SCF and its signaling pathways. Numerous factors known to have such a capacity include cytokines that are secreted from activated T cells and other immune cells including mast cells themselves. Recent studies also demonstrated that monomeric IgE binding to FcepsilonRI can enhance mast-cell survival. In this review we discuss the factors that regulate mast cell development, migration, and survival.

Figure 1

Two models of mast cell-related hematopoiesis. (A) The model by Chen et al. [12] proposes that MCPs derives mainly from MPPs. (B) Another model described by Arinobu et al. [13] proposes that intgerin β7-expressing GMPs in the bone marrow are the major source of BMCPs, a population of bipotent progenitors for basophils and mast cells, which are supposed to go through the circulation to the spleen. BMCPs expressing C/EBPα will differentiate to basophils whereas BMCPs without C/EBPα expression become MCPs. In this scheme, lineal linkages between LT-HSCs and MPPs in the bone marrow are not shown. LT-HSCs, long-term hematopoietic stem cell; ST-HSC, short-term hematopoietic stem cell; MPP, multipotential progenitor; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; MEP, megakaryocyte/erythrocyte progenitor; MK, megakaryocyte.

Figure 2

Kit signaling pathways in mast cells. This figure summarizes signaling proteins activated by Kit. Filled boxes of Kit indicate split kinase domains. Abbreviations: APS, adaptor containing PH and SH2 domains; Grb, growth factor receptor-bound protein; JAK, Janus kinase; JNK, c-Jun NH2-terminal kinase; MEK, mitogen-activated protein kinase kinase; ERK, extracellular regulated protein kinase; MITF, microphthalmia transcription factor; PI3K, phosphoinositide 3'-kinase; PLCγ, phospholipase Cγ; SCF, stem cell factor; SFK, Src family kinases; Shc, SH2-containing transforming protein C1; SHP, SH2 domain-containing phosphatase; Stat, signal transducers and activators of transcription.