PMID- 30619998
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230805
IS  - 2471-254X (Electronic)
IS  - 2471-254X (Linking)
VI  - 3
IP  - 1
DP  - 2019 Jan
TI  - Inhibition of Triggering Receptor Expressed on Myeloid Cells 1 Ameliorates 
      Inflammation and Macrophage and Neutrophil Activation in Alcoholic Liver Disease 
      in Mice.
PG  - 99-115
LID - 10.1002/hep4.1269 [doi]
AB  - Alcoholic liver disease (ALD) is characterized by macrophage and neutrophil 
      leukocyte recruitment and activation in the liver. Damage- and 
      pathogen-associated molecular patterns contribute to a self-perpetuating 
      proinflammatory state in ALD. Triggering receptor expressed on myeloid cells 1 
      (TREM-1) is a surface receptor that amplifies inflammation induced by toll-like 
      receptors (TLRs) and is expressed on neutrophils and monocytes/macrophages. We 
      hypothesized that TREM-1 signaling contributes to proinflammatory pathway 
      activation in ALD. Using an in vivo ALD model in mice, we tested the effects of 
      ligand-independent TREM-1 inhibitory peptides that were formulated into human 
      high-density lipoprotein (HDL)-mimicking complexes GF9-HDL and GA/E31-HDL. As 
      revealed in vitro, macrophages endocytosed these rationally designed complexes 
      through scavenger receptors. A 5-week alcohol feeding with the Lieber-DeCarli 
      diet in mice resulted in increased serum alanine aminotransferase (ALT), liver 
      steatosis, and increased proinflammatory cytokines in the liver. TREM-1 messenger 
      RNA (mRNA) expression was significantly increased in alcohol-fed mice, and TREM-1 
      inhibitors significantly reduced this increase. TREM-1 inhibition significantly 
      attenuated alcohol-induced spleen tyrosine kinase (SYK) activation, an early 
      event in both TLR4 and TREM-1 signaling. The TREM-1 inhibitors significantly 
      inhibited macrophage (epidermal growth factor-like module-containing mucin-like 
      hormone receptor-like 1 [F4/80], clusters of differentiation [CD]68) and 
      neutrophil (lymphocyte antigen 6 complex, locus G [Ly6G] and myeloperoxidase 
      [MPO]) markers and proinflammatory cytokines (monocyte chemoattractant protein 1 
      [MCP-1], tumor necrosis factor alpha [TNF-alpha], interleukin-1beta [IL-1beta], macrophage 
      inflammatory protein 1alpha [MIP-1alpha]) at the mRNA level compared to the HDL vehicle. 
      Administration of TREM-1 inhibitors ameliorated liver steatosis and early 
      fibrosis markers (alpha-smooth muscle actin [alphaSMA] and procollagen1alpha [Pro-Col1alpha]) at 
      the mRNA level in alcohol-fed mice. However, the HDL vehicle also reduced serum 
      ALT and some cytokine protein levels in alcohol-fed mice, indicating HDL-related 
      effects. Conclusion: HDL-delivered novel TREM-1 peptide inhibitors ameliorate 
      early phases of inflammation and neutrophil and macrophage recruitment and 
      activation in the liver and attenuate hepatocyte damage and liver steatosis. 
      TREM-1 inhibition represents a promising therapeutic approach for further 
      investigations in ALD.
FAU - Tornai, David
AU  - Tornai D
AD  - Department of Medicine University of Massachusetts Medical School Worcester MA.
FAU - Furi, Istvan
AU  - Furi I
AD  - Department of Medicine University of Massachusetts Medical School Worcester MA.
FAU - Shen, Zu T
AU  - Shen ZT
AD  - SignaBlok, Inc. Shrewsbury MA.
FAU - Sigalov, Alexander B
AU  - Sigalov AB
AD  - SignaBlok, Inc. Shrewsbury MA.
FAU - Coban, Sahin
AU  - Coban S
AD  - Department of Medicine University of Massachusetts Medical School Worcester MA.
FAU - Szabo, Gyongyi
AU  - Szabo G
AD  - Department of Medicine University of Massachusetts Medical School Worcester MA.
LA  - eng
GR  - R01 AA011576/AA/NIAAA NIH HHS/United States
PT  - Journal Article
DEP - 20181029
PL  - United States
TA  - Hepatol Commun
JT  - Hepatology communications
JID - 101695860
PMC - PMC6312652
EDAT- 2019/01/09 06:00
MHDA- 2019/01/09 06:01
PMCR- 2018/10/29
CRDT- 2019/01/09 06:00
PHST- 2018/04/11 00:00 [received]
PHST- 2018/09/07 00:00 [accepted]
PHST- 2019/01/09 06:00 [entrez]
PHST- 2019/01/09 06:00 [pubmed]
PHST- 2019/01/09 06:01 [medline]
PHST- 2018/10/29 00:00 [pmc-release]
AID - HEP41269 [pii]
AID - 10.1002/hep4.1269 [doi]
PST - epublish
SO  - Hepatol Commun. 2018 Oct 29;3(1):99-115. doi: 10.1002/hep4.1269. eCollection 2019 
      Jan.