Tribbles homolog 1 deficiency modulates function and polarization of murine bone marrow-derived macrophages

被引:26
作者
Arndt, Lilli [1 ]
Dokas, Janine [1 ]
Gericke, Martin [2 ]
Kutzner, Carl Elias [1 ]
Mueller, Silvana [1 ]
Jeromin, Franziska [1 ]
Thiery, Joachim [1 ,3 ]
Burkhardt, Ralph [1 ,3 ]
机构
[1] Univ Hosp Leipzig, Inst Lab Med Clin Chem & Mol Diagnost, Liebigstr 27, D-04103 Leipzig, Germany
[2] Univ Leipzig, Inst Anat, D-04103 Leipzig, Germany
[3] Univ Leipzig, LIFE Leipzig Res Ctr Civilizat Dis, D-04103 Leipzig, Germany
关键词
macrophage; signal transduction; migration; phagocytosis; Janus kinase (JAK); STAT transcription factor; M1; M2; polarization; REGULATES HEPATIC LIPOGENESIS; SIGNALING PATHWAYS; GENE-EXPRESSION; C/EBP-ALPHA; IMMUNE-RESPONSES; ACTIVATION; TRIB1; RECEPTOR; INFLAMMATION; CELLS;
D O I
10.1074/jbc.RA117.000703
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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/IFN 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, TNF, IL-1, 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 TGF. Mechanistically, Trib1(-/-) BMDMs displayed lower levels of Janus kinase 1 (JAK1), resulting in reduced activation of LPS/IFN-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.
引用
收藏
页码:11527 / 11536
页数:10
相关论文
共 42 条
[1]   Tribbles-1 regulates hepatic lipogenesis through posttranscriptional regulation of C/EBPα [J].
Bauer, Robert C. ;
Sasaki, Makoto ;
Cohen, Daniel M. ;
Cui, Jian ;
Smith, Mikhaila A. ;
Yenilmez, Batuhan D. ;
Steger, David J. ;
Rader, Daniel J. .
JOURNAL OF CLINICAL INVESTIGATION, 2015, 125 (10) :3809-3818
[2]   IL-4 and IL-13 employ discrete signaling pathways for target gene expression in alternatively activated monocytes/macrophages [J].
Bhattacharjee, Ashish ;
Shukla, Meenakshi ;
Yakubenko, Valentin P. ;
Mulya, Anny ;
Kundu, Suman ;
Cathcart, Martha K. .
FREE RADICAL BIOLOGY AND MEDICINE, 2013, 54 :1-16
[3]   Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm [J].
Biswas, Subhra K. ;
Mantovani, Alberto .
NATURE IMMUNOLOGY, 2010, 11 (10) :889-896
[4]   Trib1 is a lipid- and myocardial infarction-associated gene that regulates hepatic lipogenesis and VLDL production in mice [J].
Burkhardt, Ralph ;
Toh, Sue-Anne ;
Lagor, William R. ;
Birkeland, Andrew ;
Levin, Michael ;
Li, Xiaoyu ;
Robblee, Megan ;
Fedorov, Victor D. ;
Yamamoto, Masahiro ;
Satoh, Takashi ;
Akira, Shizuo ;
Kathiresan, Sekar ;
Breslow, Jan L. ;
Rader, Daniel J. .
JOURNAL OF CLINICAL INVESTIGATION, 2010, 120 (12) :4410-4414
[5]   Control of Macrophage Activation and Function by PPARs [J].
Chawla, Ajay .
CIRCULATION RESEARCH, 2010, 106 (10) :1559-1569
[6]   JAK-STAT PATHWAYS AND TRANSCRIPTIONAL ACTIVATION IN RESPONSE TO IFNS AND OTHER EXTRACELLULAR SIGNALING PROTEINS [J].
DARNELL, JE ;
KERR, IM ;
STARK, GR .
SCIENCE, 1994, 264 (5164) :1415-1421
[7]   IL-13Rα1 is a surface marker for M2 macrophages influencing their differentiation and function [J].
Dhakal, Mermagya ;
Hardaway, John C. ;
Guloglu, Fatma Betul ;
Miller, Mindy M. ;
Hoeman, Christine M. ;
Zaghouani, Adam A. ;
Wan, Xiaoxiao ;
Rowland, Linda M. ;
Cascio, Jason A. ;
Sherman, Michael P. ;
Zaghouani, Habib .
EUROPEAN JOURNAL OF IMMUNOLOGY, 2014, 44 (03) :842-855
[8]   Functional Analysis of the TRIB1 Associated Locus Linked to Plasma Triglycerides and Coronary Artery Disease [J].
Douvris, Adrianna ;
Soubeyrand, Sebastien ;
Naing, Thet ;
Martinuk, Amy ;
Nikpay, Majid ;
Williams, Andrew ;
Buick, Julie ;
Yauk, Carole ;
McPherson, Ruth .
JOURNAL OF THE AMERICAN HEART ASSOCIATION, 2014, 3 (03)
[9]   STK40 Is a Pseudokinase that Binds the E3 Ubiquitin Ligase COP1 [J].
Durzynska, Izabela ;
Xu, Xiang ;
Adelmant, Guillaume ;
Ficarro, Scott B. ;
Marto, Jarrod A. ;
Sliz, Piotrek ;
Uljon, Sacha ;
Blacklow, Stephen C. .
STRUCTURE, 2017, 25 (02) :287-294
[10]   Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease [J].
Eyers, Patrick A. ;
Keeshan, Karen ;
Kannan, Natarajan .
TRENDS IN CELL BIOLOGY, 2017, 27 (04) :284-298