Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development.
Obesity-induced chronic liver inflammation is a hallmark of nonalcoholic steatohepatitis (NASH)-an aggressive form of nonalcoholic fatty liver disease. However, it remains unclear how such a low-grade, yet persistent, inflammation is sustained in the liver. Here, we show that the macrophage phagocytic receptor TREM2, induced by hepatocyte-derived sphingosine-1-phosphate, was required for efferocytosis of lipid-laden apoptotic hepatocytes and thereby maintained liver immune homeostasis. However, prolonged hypernutrition led to the production of proinflammatory cytokines TNF and IL-1β in the liver to induce TREM2 shedding through ADAM17-dependent proteolytic cleavage. Loss of TREM2 resulted in aberrant accumulation of dying hepatocytes, thereby further augmenting proinflammatory cytokine production. This ultimately precipitated a vicious cycle that licensed chronic inflammation to drive simple steatosis transition to NASH. Therefore, impaired macrophage efferocytosis is a previously unrecognized key pathogenic event that enables chronic liver inflammation in obesity. Blocking TREM2 cleavage to restore efferocytosis may represent an effective strategy to treat NASH.
Pubmed ID: 36521495 RIS Download
Research resources used in this publication
Additional research tools detected in this publication
None foundAntibodies used in this publication
- Akt Antibody (RRID:AB_329827)
- Goat Anti-CX3CR1 Polyclonal Antibody, Unconjugated (RRID:AB_2292441)
- Rabbit Anti-TIM4 Polyclonal Antibody, Unconjugated (RRID:AB_11096753)
- PerCP/Cyanine5.5 anti-mouse Ly-6C (RRID:AB_1659241)
- Ly-6C (RRID:AB_2737749)
- Phospho-Akt (Ser473) Antibody (RRID:AB_329825)
- Recombinant Anti-HNF-4-alpha antibody [EPR16885-99] (RRID:AB_2927380)
- Mouse Osteopontin (OPN) Phycoerythrin Affinity Purified PAb (RRID:AB_10643832)
- Mouse Osteopontin (OPN) Affinity Purified Polyclonal Ab (RRID:AB_2194992)
- Chicken Anti-Goat IgG HRP Affinity Purified PAb (RRID:AB_573132)
- Anti-rat IgG, HRP-linked Antibody (RRID:AB_10694715)
- Human/Mouse Myeloperoxidase Affinity Purified Polyclonal Ab (RRID:AB_2250866)
- Alexa Fluor(R) 647 anti-mouse Tim-4 (RRID:AB_2271648)
- PE/Cyanine7 anti-mouse CD146 (RRID:AB_2563109)
- PE anti-mouse/human CD11b (RRID:AB_312791)
- CD45 (RRID:AB_2738857)
- CD45 MicroBeads, mouse (RRID:AB_2877061)
- Brilliant Violet 421(TM) anti-mouse F4/80 (RRID:AB_11203717)
- Purified anti-mouse Ly-6G (RRID:AB_1089180)
- Mouse IgM Isotype Control (F8) (RRID:AB_2927376)
- Rabbit Anti-α-Smooth Muscle Actin (RRID:AB_2734735)
- Phospho-Zap-70 (Tyr319)/Syk (Tyr352) (65E4) Rabbit mAb (RRID:AB_2218658)
- Syk (D3Z1E) XP Rabbit Antibody (RRID:AB_2687924)
- Mouse IgG VisUCyte HRP Polymer Antibody (RRID:AB_2927375)
- TREM2 (D8I4C) Rabbit mAb (RRID:AB_2721119)
- anti-Phospho-TIF1 beta (Ser824) antibody (RRID:AB_11210928)
- Goat Anti-Mouse Clecsf13 / clec4f Polyclonal antibody, Unconjugated (RRID:AB_2081339)
- SPHK2 antibody (RRID:AB_10598479)
- SPHK1 Polyclonal Antibody (RRID:AB_2804179)
- Mouse Anti-Actin, alpha-Smooth Muscle Monoclonal Antibody, Unconjugated, Clone 1A4 (RRID:AB_262054)
- Caspase-3 Antibody (RRID:AB_331439)
- Cleaved Caspase-3 (Asp175) Antibody (RRID:AB_2341188)
- Rat IgG2B Isotype Control (Clone 141945) (RRID:AB_357350)
- F4/80 Monoclonal Antibody (SP115) (RRID:AB_2537882)
- S1PR2 Polyclonal Antibody (RRID:AB_2540734)
- S1P1 Polyclonal Antibody (RRID:AB_2184729)
- Rat Anti-Mouse Trem-2b Monoclonal antibody, Unconjugated, Clone 237920 (RRID:AB_2208679)
- Anti-rabbit IgG, HRP-linked Antibody (RRID:AB_2099233)
- Human/Mouse TREM-2 Allophycocyanin MAb (Clone 237920) (RRID:AB_884527)
- Sheep Anti-Mouse Trem-2 Polyclonal antibody, Unconjugated (RRID:AB_354956)
- Rat Anti-Mouse TREM2 Monoclonal Antibody, Unconjugated, Clone RM0139-5J46 (RRID:AB_1925525)
- Donkey anti-Rat IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ Plus 647 (RRID:AB_2893138)
- Donkey anti-Goat IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ Plus 647 (RRID:AB_2762840)
- Donkey anti-Goat IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ Plus 594 (RRID:AB_2762828)
- Donkey anti-Goat IgG (H+L) Cross-Adsorbed Secondary Antibody, DyLight™ 488 (RRID:AB_2556666)
- Goat Anti-Mouse IgG (H+L) Antibody, Alexa Fluor 568 Conjugated (RRID:AB_2534072)
- Donkey anti-Sheep IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, HRP (RRID:AB_2534721)
- Donkey anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ Plus 647 (RRID:AB_2762835)
- Donkey anti-Mouse IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 488 (RRID:AB_141607)
- Donkey Anti-Mouse IgG (H+L) Antibody, Alexa Fluor ?? 594 Conjugated (RRID:AB_141633)
- Donkey anti-Rat IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 594 (RRID:AB_2535795)
- Donkey anti-Rat IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 488 (RRID:AB_2535794)
- Donkey Anti-Rabbit IgG (H+L) Antibody, Alexa Fluor ?? 594 Conjugated (RRID:AB_141637)
- Donkey Anti-Rabbit IgG (H+L) Antibody, Alexa Fluor ?? 488 Conjugated (RRID:AB_2535792)
- Mouse Anti-CD68 Monoclonal Antibody, Unconjugated, Clone KP1 (RRID:AB_307338)
- F4/80 Monoclonal Antibody (BM8), eBioscience (RRID:AB_467558)
- GAPDH (D16H11) XP Rabbit mAb (RRID:AB_10622025)
- TNF alpha Polyclonal Antibody, Biotin, eBioscience (RRID:AB_466951)
- TNF alpha Monoclonal Antibody (TN3-19.12), eBioscience (RRID:AB_468492)
- Mouse TREM-2 Biotinylated Affinity Purified PAb (RRID:AB_356109)
- ADAM10 antibody [EPR5622] (RRID:AB_10972023)
- ADAM17 Polyclonal Antibody (RRID:AB_2544871)
- PE anti-mouse CX3CR1 (RRID:AB_2564314)
- TREM2 antibody (RRID:AB_10679173)
- CD11b Monoclonal Antibody (M1/70), eFluor™ 450, eBioscience (RRID:AB_1582236)
- TREM2 (E7P8J) Rabbit mAb (Carboxy-terminal Antigen, Mouse Specific) (RRID:AB_2799888)
- CD11b MicroBeads, human and mouse (RRID:AB_2927377)
- CD16/CD32 Monoclonal Antibody (KT1632) (RRID:AB_2539396)
- Ly-6C Monoclonal Antibody (HK1.4), eFluor™ 450, eBioscience (RRID:AB_10805519)
- Ly-6G Monoclonal Antibody (1A8-Ly6g), PerCP-eFluor™ 710, eBioscience (RRID:AB_2573893)
- MHC Class II (I-A/I-E) Monoclonal Antibody (M5/114.15.2), FITC, eBioscience (RRID:AB_465233)
- CD11b Monoclonal Antibody (M1/70), eFluor™ 660, eBioscience (RRID:AB_11218507)
- Rat Anti-CD45 Monoclonal Antibody, V500 Conjugated, Clone 30-F11 (RRID:AB_10697046)
- F4/80 Monoclonal Antibody (BM8), PE, eBioscience (RRID:AB_465923)
Associated grants
- Agency: NCI NIH HHS, United States
Id: R01 CA233794 - Agency: NCI NIH HHS, United States
Id: R01 CA255621 - Agency: NIDDK NIH HHS, United States
Id: R01 DK099558
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This is a list of tools and resources that we have found mentioned in this publication.
Goat Anti-CX3CR1 Polyclonal Antibody, Unconjugated (antibody)
RRID:AB_2292441
This polyclonal targets CX3CR1
View all literature mentionsRabbit Anti-TIM4 Polyclonal Antibody, Unconjugated (antibody)
RRID:AB_11096753
This polyclonal targets Rabbit TIM4
View all literature mentionsPerCP/Cyanine5.5 anti-mouse Ly-6C (antibody)
RRID:AB_1659241
This monoclonal targets Ly-6C
View all literature mentionsPhospho-Akt (Ser473) Antibody (antibody)
RRID:AB_329825
This polyclonal targets Phospho-Akt (Ser473)
View all literature mentionsRecombinant Anti-HNF-4-alpha antibody [EPR16885-99] (antibody)
RRID:AB_2927380
This recombinant monoclonal targets HNF-4-alpha
View all literature mentionsMouse Osteopontin (OPN) Phycoerythrin Affinity Purified PAb (antibody)
RRID:AB_10643832
This polyclonal targets Mouse Osteopontin (OPN) Phycoerythrin Affinity Purified PAb
View all literature mentionsMouse Osteopontin (OPN) Affinity Purified Polyclonal Ab (antibody)
RRID:AB_2194992
This polyclonal targets Mouse Osteopontin (OPN) Affinity Purified Ab
View all literature mentionsChicken Anti-Goat IgG HRP Affinity Purified PAb (antibody)
RRID:AB_573132
This polyclonal targets Goat IgG
View all literature mentionsAnti-rat IgG, HRP-linked Antibody (antibody)
RRID:AB_10694715
This polyclonal targets rat IgG HRP-linked
View all literature mentionsHuman/Mouse Myeloperoxidase Affinity Purified Polyclonal Ab (antibody)
RRID:AB_2250866
This polyclonal targets Mouse Myeloperoxidase
View all literature mentionsAlexa Fluor(R) 647 anti-mouse Tim-4 (antibody)
RRID:AB_2271648
This monoclonal targets Tim-4
View all literature mentionsPE/Cyanine7 anti-mouse CD146 (antibody)
RRID:AB_2563109
This monoclonal targets CD146
View all literature mentionsPE anti-mouse/human CD11b (antibody)
RRID:AB_312791
This monoclonal targets CD11b
View all literature mentionsCD45 MicroBeads, mouse (antibody)
RRID:AB_2877061
This monoclonal targets CD45
View all literature mentionsBrilliant Violet 421(TM) anti-mouse F4/80 (antibody)
RRID:AB_11203717
This monoclonal targets F4/80
View all literature mentionsPurified anti-mouse Ly-6G (antibody)
RRID:AB_1089180
This monoclonal targets Ly-6G
View all literature mentionsMouse IgM Isotype Control (F8) (antibody)
RRID:AB_2927376
This monoclonal targets not applicable
View all literature mentionsRabbit Anti-α-Smooth Muscle Actin (antibody)
RRID:AB_2734735
This monoclonal targets α-Smooth Muscle Actin
View all literature mentionsPhospho-Zap-70 (Tyr319)/Syk (Tyr352) (65E4) Rabbit mAb (antibody)
RRID:AB_2218658
This monoclonal targets Phospho-Zap-70 (Tyr319)/Syk (Tyr352)
View all literature mentionsSyk (D3Z1E) XP Rabbit Antibody (antibody)
RRID:AB_2687924
This monoclonal targets Syk
View all literature mentionsMouse IgG VisUCyte HRP Polymer Antibody (antibody)
RRID:AB_2927375
This polyclonal targets IgG
View all literature mentionsTREM2 (D8I4C) Rabbit mAb (antibody)
RRID:AB_2721119
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View all literature mentionsanti-Phospho-TIF1 beta (Ser824) antibody (antibody)
RRID:AB_11210928
This polyclonal targets anti-Phospho-TIF1 beta (Ser824) antibody
View all literature mentionsGoat Anti-Mouse Clecsf13 / clec4f Polyclonal antibody, Unconjugated (antibody)
RRID:AB_2081339
This polyclonal targets Mouse CLECSF13 / CLEC4F
View all literature mentionsSPHK2 antibody (antibody)
RRID:AB_10598479
This polyclonal targets SPHK2
View all literature mentionsSPHK1 Polyclonal Antibody (antibody)
RRID:AB_2804179
This unknown targets SPHK1
View all literature mentionsMouse Anti-Actin, alpha-Smooth Muscle Monoclonal Antibody, Unconjugated, Clone 1A4 (antibody)
RRID:AB_262054
This monoclonal targets Actin, alpha, Smooth Muscle
View all literature mentionsCaspase-3 Antibody (antibody)
RRID:AB_331439
This polyclonal targets Caspase-3
View all literature mentionsCleaved Caspase-3 (Asp175) Antibody (antibody)
RRID:AB_2341188
This polyclonal targets Cleaved Caspase-3 (Asp175)
View all literature mentionsRat IgG2B Isotype Control (Clone 141945) (antibody)
RRID:AB_357350
This unknown targets Rat
View all literature mentionsF4/80 Monoclonal Antibody (SP115) (antibody)
RRID:AB_2537882
This monoclonal targets F4/80
View all literature mentionsS1PR2 Polyclonal Antibody (antibody)
RRID:AB_2540734
This unknown targets S1PR2
View all literature mentionsS1P1 Polyclonal Antibody (antibody)
RRID:AB_2184729
This unknown targets S1P1
View all literature mentionsRat Anti-Mouse Trem-2b Monoclonal antibody, Unconjugated, Clone 237920 (antibody)
RRID:AB_2208679
This monoclonal targets Mouse TREM-2b
View all literature mentionsAnti-rabbit IgG, HRP-linked Antibody (antibody)
RRID:AB_2099233
This polyclonal secondary targets IgG
View all literature mentionsHuman/Mouse TREM-2 Allophycocyanin MAb (Clone 237920) (antibody)
RRID:AB_884527
This monoclonal targets TREM-2
View all literature mentionsSheep Anti-Mouse Trem-2 Polyclonal antibody, Unconjugated (antibody)
RRID:AB_354956
This polyclonal targets Mouse TREM-2
View all literature mentionsRat Anti-Mouse TREM2 Monoclonal Antibody, Unconjugated, Clone RM0139-5J46 (antibody)
RRID:AB_1925525
This monoclonal targets Mouse TREM2
View all literature mentionsDonkey anti-Rat IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ Plus 647 (antibody)
RRID:AB_2893138
This polyclonal secondary targets IgG (H+L)
View all literature mentionsDonkey anti-Goat IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ Plus 647 (antibody)
RRID:AB_2762840
This polyclonal secondary targets IgG (H+L)
View all literature mentionsDonkey anti-Goat IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ Plus 594 (antibody)
RRID:AB_2762828
This polyclonal secondary targets IgG (H+L)
View all literature mentionsDonkey anti-Goat IgG (H+L) Cross-Adsorbed Secondary Antibody, DyLight™ 488 (antibody)
RRID:AB_2556666
This polyclonal secondary targets IgG (H+L)
View all literature mentionsGoat Anti-Mouse IgG (H+L) Antibody, Alexa Fluor 568 Conjugated (antibody)
RRID:AB_2534072
This unknown targets IgG (H+L)
View all literature mentionsDonkey anti-Sheep IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, HRP (antibody)
RRID:AB_2534721
This polyclonal secondary targets IgG (H+L)
View all literature mentionsDonkey anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ Plus 647 (antibody)
RRID:AB_2762835
This polyclonal secondary targets IgG (H+L)
View all literature mentionsDonkey anti-Mouse IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 488 (antibody)
RRID:AB_141607
This polyclonal secondary targets IgG (H+L)
View all literature mentionsDonkey Anti-Mouse IgG (H+L) Antibody, Alexa Fluor ?? 594 Conjugated (antibody)
RRID:AB_141633
This unknown targets Mouse IgG (H+L)
View all literature mentionsDonkey anti-Rat IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 594 (antibody)
RRID:AB_2535795
This polyclonal secondary targets IgG (H+L)
View all literature mentionsDonkey anti-Rat IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 488 (antibody)
RRID:AB_2535794
This polyclonal secondary targets IgG (H+L)
View all literature mentionsDonkey Anti-Rabbit IgG (H+L) Antibody, Alexa Fluor ?? 594 Conjugated (antibody)
RRID:AB_141637
This unknown targets Rabbit IgG (H+L)
View all literature mentionsDonkey Anti-Rabbit IgG (H+L) Antibody, Alexa Fluor ?? 488 Conjugated (antibody)
RRID:AB_2535792
This unknown targets Rabbit IgG (H+L)
View all literature mentionsMouse Anti-CD68 Monoclonal Antibody, Unconjugated, Clone KP1 (antibody)
RRID:AB_307338
This monoclonal targets CD68
View all literature mentionsF4/80 Monoclonal Antibody (BM8), eBioscience (antibody)
RRID:AB_467558
This monoclonal targets F4/80
View all literature mentionsGAPDH (D16H11) XP Rabbit mAb (antibody)
RRID:AB_10622025
This monoclonal targets GAPDH
View all literature mentionsTNF alpha Polyclonal Antibody, Biotin, eBioscience (antibody)
RRID:AB_466951
This unknown targets TNF alpha
View all literature mentionsTNF alpha Monoclonal Antibody (TN3-19.12), eBioscience (antibody)
RRID:AB_468492
This monoclonal targets TNF alpha
View all literature mentionsMouse TREM-2 Biotinylated Affinity Purified PAb (antibody)
RRID:AB_356109
This polyclonal targets Mouse TREM-2 ylated Affinity Purified PAb
View all literature mentionsADAM10 antibody [EPR5622] (antibody)
RRID:AB_10972023
This monoclonal targets ADAM10 antibody [EPR5622]
View all literature mentionsADAM17 Polyclonal Antibody (antibody)
RRID:AB_2544871
This unknown targets ADAM17
View all literature mentionsPE anti-mouse CX3CR1 (antibody)
RRID:AB_2564314
This monoclonal targets CX3CR1
View all literature mentionsTREM2 antibody (antibody)
RRID:AB_10679173
This polyclonal targets TREM2 antibody
View all literature mentionsCD11b Monoclonal Antibody (M1/70), eFluor™ 450, eBioscience (antibody)
RRID:AB_1582236
This monoclonal targets CD11b
View all literature mentionsTREM2 (E7P8J) Rabbit mAb (Carboxy-terminal Antigen, Mouse Specific) (antibody)
RRID:AB_2799888
This monoclonal targets TREM2
View all literature mentionsCD11b MicroBeads, human and mouse (antibody)
RRID:AB_2927377
This monoclonal targets CD11b
View all literature mentionsCD16/CD32 Monoclonal Antibody (KT1632) (antibody)
RRID:AB_2539396
This monoclonal targets CD16/CD32
View all literature mentionsLy-6C Monoclonal Antibody (HK1.4), eFluor™ 450, eBioscience (antibody)
RRID:AB_10805519
This monoclonal targets Ly-6C
View all literature mentionsLy-6G Monoclonal Antibody (1A8-Ly6g), PerCP-eFluor™ 710, eBioscience (antibody)
RRID:AB_2573893
This monoclonal targets Ly-6G
View all literature mentionsMHC Class II (I-A/I-E) Monoclonal Antibody (M5/114.15.2), FITC, eBioscience (antibody)
RRID:AB_465233
This monoclonal targets MHC Class II (I-A/I-E)
View all literature mentionsCD11b Monoclonal Antibody (M1/70), eFluor™ 660, eBioscience (antibody)
RRID:AB_11218507
This monoclonal targets CD11b
View all literature mentionsRat Anti-CD45 Monoclonal Antibody, V500 Conjugated, Clone 30-F11 (antibody)
RRID:AB_10697046
This monoclonal targets Rat CD45 V500 Clone 30-F11
View all literature mentionsF4/80 Monoclonal Antibody (BM8), PE, eBioscience (antibody)
RRID:AB_465923
This monoclonal targets F4/80
View all literature mentionsIngenuity Pathway Analysis (pathway analysis tool)
RRID:SCR_008653
A web-based software application that enables users to analyze, integrate, and understand data derived from gene expression, microRNA, and SNP microarrays, metabolomics, proteomics, and RNA-Seq experiments, and small-scale experiments that generate gene and chemical lists. Users can search for targeted information on genes, proteins, chemicals, and drugs, and build interactive models of experimental systems. IPA allows exploration of molecular, chemical, gene, protein and miRNA interactions, creation of custom molecular pathways, and the ability to view and modify metabolic, signaling, and toxicological canonical pathways. In addition to the networks and pathways that can be created, IPA can provide multiple layering of additional information, such as drugs, disease genes, expression data, cellular functions and processes, or a researchers own genes or chemicals of interest.
View all literature mentionsFlowJo (software resource)
RRID:SCR_008520
Software for single-cell flow cytometry analysis. Its functions include management, display, manipulation, analysis and publication of the data stream produced by flow and mass cytometers.
View all literature mentionsGraphPad Prism (software resource)
RRID:SCR_002798
Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
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