PMID- 32429067
OWN - NLM
STAT- MEDLINE
DCOM- 20210224
LR  - 20210224
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 9
IP  - 5
DP  - 2020 May 15
TI  - TNFalpha Rescues Dendritic Cell Development in Hematopoietic Stem and Progenitor 
      Cells Lacking C/EBPalpha.
LID - 10.3390/cells9051223 [doi]
LID - 1223
AB  - Dendritic cells (DCs) are crucial effectors of the immune system, which are 
      formed from hematopoietic stem and progenitor cells (HSPCs) by a multistep 
      process regulated by cytokines and distinct transcriptional mechanisms. C/EBPalpha is 
      an important myeloid transcription factor, but its role in DC formation is not 
      well defined. Using a Cebpa(Cre)-EYFP reporter mouse model, we show that the 
      majority of splenic conventional DCs are derived from Cebpa-expressing HSPCs. 
      Furthermore, HSPCs isolated from Cebpa knockout (KO) mice exhibited a marked 
      reduced ability to form mature DCs after in vitro culture with FLT3L. 
      Differentiation analysis revealed that C/EBPalpha was needed for the formation of 
      monocytic dendritic progenitors and their transition to common dendritic 
      progenitors. Gene expression analysis and cytokine profiling of culture 
      supernatants showed significant downregulation of inflammatory cytokines, 
      including TNFalpha and IL-1beta as well as distinct chemokines in KO HSPCs. In addition, 
      TNFalpha-induced genes were among the most dysregulated genes in KO HSPCs. 
      Intriguingly, supplementation of in vitro cultures with TNFalpha at least partially 
      rescued DC formation of KO HSPCs, resulting in fully functional, mature DCs. In 
      conclusion, these results reveal an important role of C/EBPalpha in early DC 
      development, which in part can be substituted by the inflammatory cytokine TNFalpha.
FAU - Anirudh, Subramanian
AU  - Anirudh S
AUID- ORCID: 0000-0001-7102-9968
AD  - Division of Hematology, Medical University of Graz, Auenbruggerplatz 38, A-8036 
      Graz, Austria.
FAU - Rosenberger, Angelika
AU  - Rosenberger A
AD  - Division of Hematology, Medical University of Graz, Auenbruggerplatz 38, A-8036 
      Graz, Austria.
FAU - Schwarzenberger, Elke
AU  - Schwarzenberger E
AD  - Division of Immunology and Pathophysiology, Otto Loewi Research Center for 
      Vascular Biology, Immunology and Inflammation, Medical University of Graz, 
      Heinrichstrasse 31, A-8010 Graz, Austria.
FAU - Schaefer, Carolin
AU  - Schaefer C
AD  - Division of Hematology, Medical University of Graz, Auenbruggerplatz 38, A-8036 
      Graz, Austria.
FAU - Strobl, Herbert
AU  - Strobl H
AD  - Division of Immunology and Pathophysiology, Otto Loewi Research Center for 
      Vascular Biology, Immunology and Inflammation, Medical University of Graz, 
      Heinrichstrasse 31, A-8010 Graz, Austria.
FAU - Zebisch, Armin
AU  - Zebisch A
AUID- ORCID: 0000-0002-4861-7021
AD  - Division of Hematology, Medical University of Graz, Auenbruggerplatz 38, A-8036 
      Graz, Austria.
AD  - Division of Pharmacology, Otto-Loewi-Research Center for Vascular Biology, 
      Immunology and Inflammation, Medical University of Graz, Universitatsplatz 4, 
      A-8010 Graz, Austria.
FAU - Sill, Heinz
AU  - Sill H
AUID- ORCID: 0000-0003-0993-4371
AD  - Division of Hematology, Medical University of Graz, Auenbruggerplatz 38, A-8036 
      Graz, Austria.
FAU - Wolfler, Albert
AU  - Wolfler A
AUID- ORCID: 0000-0002-3112-9857
AD  - Division of Hematology, Medical University of Graz, Auenbruggerplatz 38, A-8036 
      Graz, Austria.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200515
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (CCAAT-Enhancer-Binding Protein-alpha)
RN  - 0 (Chemokines)
RN  - 0 (Membrane Proteins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (flt3 ligand protein)
SB  - IM
MH  - Animals
MH  - CCAAT-Enhancer-Binding Protein-alpha/*metabolism
MH  - Chemokines/metabolism
MH  - Dendritic Cells/*cytology/drug effects/metabolism
MH  - Hematopoietic Stem Cells/*cytology/drug effects/*metabolism
MH  - Membrane Proteins/pharmacology
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Tumor Necrosis Factor-alpha/*pharmacology
PMC - PMC7291045
OTO - NOTNLM
OT  - C/EBPalpha
OT  - TNFalpha
OT  - dendritic cell development
OT  - monocytic dendritic cell progenitors
COIS- The authors declare no conflict of interest.
EDAT- 2020/05/21 06:00
MHDA- 2021/02/25 06:00
PMCR- 2020/05/01
CRDT- 2020/05/21 06:00
PHST- 2020/02/13 00:00 [received]
PHST- 2020/05/04 00:00 [revised]
PHST- 2020/05/14 00:00 [accepted]
PHST- 2020/05/21 06:00 [entrez]
PHST- 2020/05/21 06:00 [pubmed]
PHST- 2021/02/25 06:00 [medline]
PHST- 2020/05/01 00:00 [pmc-release]
AID - cells9051223 [pii]
AID - cells-09-01223 [pii]
AID - 10.3390/cells9051223 [doi]
PST - epublish
SO  - Cells. 2020 May 15;9(5):1223. doi: 10.3390/cells9051223.