PMID- 29899113
OWN - NLM
STAT- MEDLINE
DCOM- 20190204
LR  - 20211204
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 293
IP  - 29
DP  - 2018 Jul 20
TI  - Tribbles homolog 1 deficiency modulates function and polarization of murine bone 
      marrow-derived macrophages.
PG  - 11527-11536
LID - S0021-9258(20)31574-X [pii]
LID - 10.1074/jbc.RA117.000703 [doi]
AB  - Macrophages are essential for innate immunity and inflammatory responses and 
      differentiate into various functional phenotypes. Tribbles homolog 1 (Trib1), a 
      member of the mammalian Tribbles homolog pseudokinase family, has been implicated 
      in regulation of cell differentiation, proliferation, and metabolism, but its 
      role in macrophage biology has not been fully elucidated. Here, we investigated 
      the consequences of Trib1 deficiency on macrophage functions and M1/M2 
      polarization. Bone marrow-derived macrophages (BMDMs) from Trib1-deficient 
      (Trib1(-/-)) mice exhibited elevated phagocytic capacity, correlating with 
      up-regulation of several scavenger receptors. Concomitantly, uptake of modified 
      low-density lipoprotein was increased in Trib1(-/-) BMDMs. Trib1(-/-) macrophages 
      also exhibited diminished migration in the presence of the chemokine MCP-1, 
      associated with reduced expression of the MCP-1 receptor Ccr2 Furthermore, Trib1 
      deficiency attenuated the response of BMDMs to both M1 and M2 stimuli; induction 
      of the M1-marker genes Il6, Il1b, and Nos2 upon LPS/IFNgamma stimulation and of the 
      M2-marker genes Cd206, Fizz1, and Arg1 upon IL-4 stimulation was reduced. 
      Functionally, Trib1 deficiency decreased secretion of proinflammatory cytokines 
      (IL-6, TNFalpha, IL-1beta, and CXCL1) and reduced nitric oxide and reactive oxygen 
      species production in M1-polarized macrophages. Supporting the attenuated M2 
      phenotype, IL-4-stimulated Trib1(-/-) macrophages secreted less IL-10 and TGFbeta. 
      Mechanistically, Trib1(-/-) BMDMs displayed lower levels of Janus kinase 1 
      (JAK1), resulting in reduced activation of LPS/IFNgamma-mediated STAT1 signaling. 
      Likewise, decreased levels of JAK1 along with lower activation of STAT6 and STAT3 
      were observed in M2-polarized Trib1(-/-) BMDMs. Our findings suggest that Trib1 
      extensively controls macrophage M1/M2 polarization via the JAK/STAT signaling 
      pathway.
CI  - (c) 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Arndt, Lilli
AU  - Arndt L
AD  - Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, 
      University Hospital Leipzig, 04103 Leipzig, Germany.
FAU - Dokas, Janine
AU  - Dokas J
AD  - Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, 
      University Hospital Leipzig, 04103 Leipzig, Germany.
FAU - Gericke, Martin
AU  - Gericke M
AD  - Institute of Anatomy, University of Leipzig, 04103 Leipzig, Germany.
FAU - Kutzner, Carl Elias
AU  - Kutzner CE
AD  - Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, 
      University Hospital Leipzig, 04103 Leipzig, Germany.
FAU - Muller, Silvana
AU  - Muller S
AD  - Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, 
      University Hospital Leipzig, 04103 Leipzig, Germany.
FAU - Jeromin, Franziska
AU  - Jeromin F
AD  - Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, 
      University Hospital Leipzig, 04103 Leipzig, Germany.
FAU - Thiery, Joachim
AU  - Thiery J
AD  - Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, 
      University Hospital Leipzig, 04103 Leipzig, Germany; LIFE-Leipzig Research Center 
      for Civilization Diseases, University of Leipzig, 04103 Leipzig, Germany.
FAU - Burkhardt, Ralph
AU  - Burkhardt R
AD  - Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, 
      University Hospital Leipzig, 04103 Leipzig, Germany; LIFE-Leipzig Research Center 
      for Civilization Diseases, University of Leipzig, 04103 Leipzig, Germany. 
      Electronic address: ralph.burkhardt@medizin.uni-leipzig.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180613
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (STAT Transcription Factors)
RN  - 0 (Trib1 protein, mouse)
RN  - EC 2.7.10.2 (Janus Kinase 1)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Bone Marrow Cells/cytology
MH  - *Cell Movement
MH  - *Cell Polarity
MH  - *Gene Deletion
MH  - Intracellular Signaling Peptides and Proteins/*genetics/metabolism
MH  - Janus Kinase 1/metabolism
MH  - Macrophages/*cytology/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - *Phagocytosis
MH  - Protein Serine-Threonine Kinases/*antagonists & inhibitors/genetics/metabolism
MH  - STAT Transcription Factors/metabolism
MH  - Signal Transduction
PMC - PMC6065162
OTO - NOTNLM
OT  - Janus kinase (JAK)
OT  - M1/M2
OT  - STAT transcription factor
OT  - macrophage
OT  - migration
OT  - phagocytosis
OT  - polarization
OT  - signal transduction
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article
EDAT- 2018/06/15 06:00
MHDA- 2019/02/05 06:00
PMCR- 2019/07/20
CRDT- 2018/06/15 06:00
PHST- 2017/11/01 00:00 [received]
PHST- 2018/05/23 00:00 [revised]
PHST- 2018/06/15 06:00 [pubmed]
PHST- 2019/02/05 06:00 [medline]
PHST- 2018/06/15 06:00 [entrez]
PHST- 2019/07/20 00:00 [pmc-release]
AID - S0021-9258(20)31574-X [pii]
AID - RA117.000703 [pii]
AID - 10.1074/jbc.RA117.000703 [doi]
PST - ppublish
SO  - J Biol Chem. 2018 Jul 20;293(29):11527-11536. doi: 10.1074/jbc.RA117.000703. Epub 
      2018 Jun 13.