The Medium-Chain Fatty Acid Receptor GPR84 Mediates Myeloid Cell Infiltration Promoting Steatohepatitis and Fibrosis
Abstract
:1. Introduction
2. Material and Methods
2.1. Human Liver Samples
2.2. Animal Experiments
2.3. Pharmacological Agents and Administration
2.4. Induction of Liver Injury and Pharmacological Treatment
2.5. Phenotypic Assessment and Model Endpoints
2.6. Stimulation and Chemotaxis of Primary Human Monocytes, Macrophages and Neutrophils
2.7. Chemotaxis Assays for Murine Bone-Marrow Monocytes and Neutrophils
2.8. In Situ Hybridization
2.9. Statistics
3. Results
3.1. Inflammatory Induction of GPR84 in Mice and Men Promotes Myeloid Cell Chemotaxis
3.2. Pharmacological Antagonism of GPR84 Inhibits the Infiltration of Hepatic Neutrophils and Macrophages in Acute Liver Injury
3.3. Reduced Hepatic Neutrophil and Macrophage Accumulation by GPR84 Inhibition Ameliorates Steatohepatitis and Fibrosis in Dietary Models of Fatty Liver Disease
3.4. Therapeutic Inhibition of GPR84 Reduces Macrophage Accumulation and Hepatic Fibrosis in CCl4 Induced Chronic Liver Injury
4. Discussion
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Assay Type | Cpd A | Cpd B |
---|---|---|
hGTPgS (IC50 nM) Hek293-hGPR84 cell membrane, DIM (EC80) | 54 nM | 11 nM |
cAMP HTRF assay (IC50 nM) CHO-K1-hGPR84 cell membrane, Capric acid (EC80 = 61.7 µM) | 7 nM | 2 nM |
cAMP HTRF assay (IC50 nM) CHO-K1-mGPR84 cell membrane, Capric acid (EC80 = 61.7 µM) | 305 nM | 34 nM |
Human Neutrophil chemotaxis (IC50 nM), Embelin | 11 nM | 31 nM |
Rat Neutrophil chemotaxis (IC50 nM), Embelin | 111 nM | 94 nM |
Healthy | NAFLD | |
---|---|---|
n | 5 | 19 |
Age, median (± IQR) years | 41 (± 20) | 59 (± 14.5) |
ALT, median (± IQR) IU/l | n.a. | 35 (± 38.5) |
AST, median (± IQR) IU/l | n.a. | 44.5 (± 43) |
Liver Histology | ||
Kleiner score Steatosis | 0 (± 0.0) | 1.5 (± 1) |
Kleiner score Ballooning | 0 (± 0.0) | 1 (± 1) |
Kleiner score Inflammation | 0 (± 0.0) | 1.5 (± 1) |
Kleiner NAS score | 0 (± 0.0) | 4.5 (± 2.4) |
Kleiner Fibrosis stage | 0 (± 0.75) | 2 (± 1.5) |
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Share and Cite
Puengel, T.; De Vos, S.; Hundertmark, J.; Kohlhepp, M.; Guldiken, N.; Pujuguet, P.; Auberval, M.; Marsais, F.; Shoji, K.F.; Saniere, L.; et al. The Medium-Chain Fatty Acid Receptor GPR84 Mediates Myeloid Cell Infiltration Promoting Steatohepatitis and Fibrosis. J. Clin. Med. 2020, 9, 1140. https://doi.org/10.3390/jcm9041140
Puengel T, De Vos S, Hundertmark J, Kohlhepp M, Guldiken N, Pujuguet P, Auberval M, Marsais F, Shoji KF, Saniere L, et al. The Medium-Chain Fatty Acid Receptor GPR84 Mediates Myeloid Cell Infiltration Promoting Steatohepatitis and Fibrosis. Journal of Clinical Medicine. 2020; 9(4):1140. https://doi.org/10.3390/jcm9041140
Chicago/Turabian StylePuengel, Tobias, Steve De Vos, Jana Hundertmark, Marlene Kohlhepp, Nurdan Guldiken, Philippe Pujuguet, Marielle Auberval, Florence Marsais, Kenji F. Shoji, Laurent Saniere, and et al. 2020. "The Medium-Chain Fatty Acid Receptor GPR84 Mediates Myeloid Cell Infiltration Promoting Steatohepatitis and Fibrosis" Journal of Clinical Medicine 9, no. 4: 1140. https://doi.org/10.3390/jcm9041140