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1.
Immunity ; 50(6): 1467-1481.e6, 2019 06 18.
Article in English | MEDLINE | ID: mdl-31201093

ABSTRACT

Tissue-resident macrophages are receptive to specific signals concentrated in cellular niches that direct their cell differentiation and maintenance genetic programs. Here, we found that deficiency of the cytokine RANKL in lymphoid tissue organizers and marginal reticular stromal cells of lymph nodes resulted in the loss of the CD169+ sinusoidal macrophages (SMs) comprising the subcapsular and the medullary subtypes. Subcapsular SM differentiation was impaired in mice with targeted RANK deficiency in SMs. Temporally controlled RANK removal in lymphatic endothelial cells (LECs) revealed that lymphatic RANK activation during embryogenesis and shortly after birth was required for the differentiation of both SM subtypes. Moreover, RANK expression by LECs was necessary for SM restoration after inflammation-induced cell loss. Thus, cooperation between mesenchymal cells and LECs shapes a niche environment that supports SM differentiation and reconstitution after inflammation.


Subject(s)
Cytokines/metabolism , Lymph Nodes/cytology , Macrophages/metabolism , Mesenchymal Stem Cells/metabolism , RANK Ligand/metabolism , Receptor Activator of Nuclear Factor-kappa B/metabolism , Stromal Cells/metabolism , Animals , Biomarkers , Cell Differentiation , Cellular Microenvironment , Immunophenotyping , Macrophages/immunology , Mice , Mice, Transgenic , Signal Transduction
2.
PLoS One ; 11(3): e0151848, 2016.
Article in English | MEDLINE | ID: mdl-27010197

ABSTRACT

Microenvironment and activation signals likely imprint heterogeneity in the lymphatic endothelial cell (LEC) population. Particularly LECs of secondary lymphoid organs are exposed to different cell types and immune stimuli. However, our understanding of the nature of LEC activation signals and their cell source within the secondary lymphoid organ in the steady state remains incomplete. Here we show that integrin alpha 2b (ITGA2b), known to be carried by platelets, megakaryocytes and hematopoietic progenitors, is expressed by a lymph node subset of LECs, residing in medullary, cortical and subcapsular sinuses. In the subcapsular sinus, the floor but not the ceiling layer expresses the integrin, being excluded from ACKR4+ LECs but overlapping with MAdCAM-1 expression. ITGA2b expression increases in response to immunization, raising the possibility that heterogeneous ITGA2b levels reflect variation in exposure to activation signals. We show that alterations of the level of receptor activator of NF-κB ligand (RANKL), by overexpression, neutralization or deletion from stromal marginal reticular cells, affected the proportion of ITGA2b+ LECs. Lymph node LECs but not peripheral LECs express RANK. In addition, we found that lymphotoxin-ß receptor signaling likewise regulated the proportion of ITGA2b+ LECs. These findings demonstrate that stromal reticular cells activate LECs via RANKL and support the action of hematopoietic cell-derived lymphotoxin.


Subject(s)
Endothelial Cells/immunology , Lymph Nodes/cytology , Platelet Membrane Glycoprotein IIb/immunology , RANK Ligand/immunology , Animals , Cells, Cultured , Endothelial Cells/cytology , Fibronectins/immunology , Lymph Nodes/immunology , Lymphotoxin-beta/immunology , Mice, Inbred C57BL , Signal Transduction
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