Csf1r or Mer inhibition delays liver regeneration via suppression of Kupffer cells.
Animals
Antigens, Differentiation
/ analysis
Antigens, Differentiation, B-Lymphocyte
/ metabolism
Hepatectomy
Kupffer Cells
/ cytology
Liver Regeneration
/ drug effects
Macrophages
/ metabolism
Mice
Protein Kinase Inhibitors
/ pharmacology
Receptor Protein-Tyrosine Kinases
/ antagonists & inhibitors
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
/ antagonists & inhibitors
Receptors, Immunologic
/ antagonists & inhibitors
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2019
2019
Historique:
received:
07
01
2019
accepted:
17
04
2019
entrez:
3
5
2019
pubmed:
3
5
2019
medline:
28
1
2020
Statut:
epublish
Résumé
Murine Kupffer cells (KCs) comprise CD11bhi and F4/80hi subsets. Tissue-resident macrophages are known to express the tyrosine kinase receptors colony-stimulating factor 1 receptor (Csf1r) and Mer. However, the expression of Csf1r and Mer on KC subsets and the importance of these tyrosine kinases during liver regeneration (LR) are unknown. KCs from wild-type and Csf1r-GFP mice were characterized by flow cytometry. Partial hepatectomy (PH) was performed in mice treated with clodronate liposomes, a Csf1r small molecule inhibitor or depleting antibody, or a small molecule Mer inhibitor. Sera and livers were analyzed. The function of sorted KC subsets was tested in vitro. Mer was specifically expressed on tissue-resident F4/80hi KCs, 55% of which also expressed Csf1r. Mer+Csf1r+ and Mer+Csf1r- KCs had distinct expression of macrophage markers. Csf1r inhibition in mice reduced F4/80hi KCs by approximately 50%, but did not affect CD11bhi KCs. Clodronate liposomes depleted F4/80hi KCs, but also altered levels of other intrahepatic leukocytes. Csf1r inhibition delayed LR, as demonstrated by a 20% reduction in liver-to-body weight ratios 7 days after PH. At 36h after PH, Csf1r inhibition increased serum ALT and histological liver injury, and decreased liver cell proliferation. A small molecule inhibitor of Mer did not alter the percentage of KCs or their proliferation and just modestly delayed LR. In vitro, Csf1r or Mer inhibition did not decrease KC viability, but did attenuate their cytokine response to stimulation. F4/80hi KCs are Mer+ and can be subdivided based on Csf1r expression. Csf1r or Mer inhibition each reduces KC cytokine production and delays LR.
Identifiants
pubmed: 31042769
doi: 10.1371/journal.pone.0216275
pii: PONE-D-19-00570
pmc: PMC6493758
doi:
Substances chimiques
Antigens, Differentiation
0
Antigens, Differentiation, B-Lymphocyte
0
Csf1r protein, mouse
0
Protein Kinase Inhibitors
0
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
0
Receptors, Immunologic
0
monocyte-macrophage differentiation antigen
0
mouse erythrocyte receptor
0
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0216275Subventions
Organisme : NCI NIH HHS
ID : F32 CA186534
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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