RT Journal Article
SR Electronic
T1 Mucosal Mast Cell–Specific Gene Expression Is Promoted by Interdependent Action of Notch and TGF-β Signaling
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP 3098
OP 3106
DO 10.4049/jimmunol.2100112
VO 207
IS 12
A1 Nakano, Nobuhiro
A1 Saida, Kazuki
A1 Hara, Mutsuko
A1 Izawa, Kumi
A1 Ando, Tomoaki
A1 Kaitani, Ayako
A1 Kasakura, Kazumi
A1 Yashiro, Takuya
A1 Nishiyama, Chiharu
A1 Ogawa, Hideoki
A1 Kitaura, Jiro
A1 Okumura, Ko
YR 2021
UL http://www.jimmunol.org/content/207/12/3098.abstract
AB Notch signaling enhances SMAD-dependent expression of mucosal mast cell markers.Notch signaling regulates epigenetic modification of mucosal mast cell marker genes.Notch signaling promotes the nuclear localization of SMADs 3 and 4 in mast cells.Rodent mast cells are classified into two major subsets, mucosal mast cells (MMCs) and connective tissue mast cells. MMCs arise from mast cell progenitors that are mobilized from the bone marrow to mucosal tissues in response to allergic inflammation or helminth infection. TGF-β is known as an inducer of MMC differentiation in mucosal tissues, but we have previously found that Notch receptor–mediated signaling also leads to the differentiation. Here, we examined the relationship between Notch and TGF-β signaling in MMC differentiation using mouse bone marrow-derived mast cells (BMMCs). We found that the coexistence of Notch and TGF-β signaling markedly upregulates the expression of MMC markers, mouse mast cell protease (mMCP)-1, mMCP-2, and αE integrin/CD103, more than Notch or TGF-β signaling alone, and that their signals act interdependently to induce these marker expressions. Notch and TGF-β–mediated transcription of MMC marker genes were both dependent on the TGF-β signaling transducer SMAD4. In addition, we also found that Notch signaling markedly upregulated mMCP-1 and mMCP-2 expression levels through epigenetic deregulation of the promoter regions of these genes, but did not affect the promoter of the CD103-encoding gene. Moreover, forced expression of the constitutively active Notch2 intracellular domain in BMMCs showed that Notch signaling promotes the nuclear localization of SMADs 3 and 4 and causes SMAD4-dependent gene transcription. These findings indicate that Notch and TGF-β signaling play interdependent roles in inducing the differentiation and maturation of MMCs. These roles may contribute to the rapid expansion of the number of MMCs during allergic mucosal inflammation.