Abstract
Background:
Mast cell development is the foundation for mast cell-involved diseases.
Results:
P38α modulates both mast cell differentiation from progenitor cells and SCF-induced migration in fully committed mast cells.
Conclusion:
P38α plays a critical role in mast cell development and function.
Significance:
P38α is a novel regulator of mast cell development, and interfering with the P38α pathway may present a new therapeutic strategy for mast cell-mediated diseases.
Mast cells mediate a range of immune responses. However, the mechanisms that contribute to their development remain poorly understood. Here, using a P38α conditional knockout system, we provide evidence to suggest that P38α plays critical roles in regulating mast cell differentiation and migration via distinct mechanisms. Induced deletion of P38α in bone marrow cells retards the maturation of mast cells in part by inhibiting the activation of cAMP response element-binding protein and expression of microphthalmia-associated transcription factor, which encourages the generation of basophils over mast cells. In fully differentiated mast cells, absence of P38α inhibits stem cell factor-induced activation of Akt and ERK, which is associated with reduced chemotaxis.
In vivo
, conditional deletion of P38α results in reduced numbers of mast cells in certain tissues and a failure to reconstitute these cells in
W
sh
mice transplanted with P38α
−/−
Lin
−
c-kit
+
Sca-1
+
(LKS
+
) cells. Our findings suggest that P38α plays a dual role in mast cell development by regulating IL-3-induced differentiation of mast cell progenitor cells as well as by regulating stem cell factor-induced migration of fully differentiated mast cells.
