The transcription factor NR4A3 controls CD103+ dendritic cell migration.
The transcription factor NR4A3 (also known as NOR-1) is a member of the Nr4a family of nuclear receptors and is expressed in myeloid and lymphoid cells. Here, we have shown that Nr4a3 is essential for the migration of CD103+ dendritic cells (DCs) to lymph nodes (LNs). Nr4a3-deficient mice had very few CD103+ migratory DCs (mDCs) present in LNs, and mixed-chimera studies revealed that this migratory defect was cell intrinsic. We further found that CD103+ DCs from Nr4a3-deficient mice displayed a marked loss of surface expression of the chemokine CCR7. This defect in CCR7 expression was confined to CD103+ DCs, as CCR7 expression on T lymphocytes was unaffected. Moreover, CCR7 was not induced on CD103+ DCs from Nr4a3-deficient mice in response to either administration of the TLR7 agonist R848 or infection with Citrobacter rodentium in vivo. The transcription factor FOXO1 has been shown to regulate CCR7 expression. We found that FOXO1 protein was reduced in Nr4a3-deficient DCs through an AKT-dependent mechanism. Further, we found a requirement for NR4A3 in the maintenance of homeostatic mitochondrial function in CD103+ DCs, although this is likely independent of the NR4A3/FOXO1/CCR7 axis in the regulation of DC migration. Thus, NR4A3 plays an important role in the regulation of CD103+ mDCs by regulating CCR7-dependent cell migration.
Kiwon
K
Park
Zbigniew
Z
Mikulski
Goo-Young
GY
Seo
Aleksander Y
AY
Andreyev
Paola
P
Marcovecchio
Amy
A
Blatchley
Mitchell
M
Kronenberg
Catherine C
CC
Hedrick
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D044082:Citrobacter rodentium / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D004756:Enterobacteriaceae Infections / Q000235:genetics / Q000276:immunology; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D007093:Imidazoles / Q000494:pharmacology; D039001:Integrin alpha Chains / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology*; D054400:Receptors, CCR7 / Q000235:genetics / Q000276:immunology; D011987:Receptors, Steroid / Q000235:genetics / Q000276:immunology*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D015703:Antigens, CD; C515371:Ccr7 protein, mouse; D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; D007093:Imidazoles; D039001:Integrin alpha Chains; D009419:Nerve Tissue Proteins; C490411:Nr4a3 protein, mouse; D054400:Receptors, CCR7; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; C091367:alpha E integrins; C402365:resiquimod