Functional role of macrophage subsets in acetaminophen-induced acute liver failure and therapeutic implica-tions of its modulation by chemokine pathways
Final Report Abstract
In this proposal, we investigated the dynamics and differentiation of macrophage subpopulations as well as the functional involvement of the chemokine receptor CCR2 in APAP-induced and other models of acute liver injury. The therapeutic potential of blocking CCL2, the main CCR2 ligand, and of CCR2 itself was tested using innovative pharmacological inhibitors in this mouse model and thus enabled translational approaches for clinical applications. Specific aims and results were: 1. Characterization and dynamics of macrophage subsets and CCR2-dependent inflammation in APAP- induced liver injury (we had used transgenic mouse strains in acute liver injury models, intravital multiphoton microscopy imaging of liver for CCR2+ monocytes, functional validation by adoptive transfers); 2. exploration of the effects of pre-existing steatosis for monocyte recruitment and differentiation (Western-diet [WD] steatosis model was partially protected from APAP injury, adoptive transfer of WD-derived macrophages protected chow diet fed animals from APAP injury); 3. molecular mechanisms of macrophage differentiation in APAP-induced liver injury (we identified key effector pathways using extensive phenotyping by FACS and Nanostring-based multiplex gene analyses [from sorted populations], single-cell RNA sequencing revealed a unique NAFLD- inflammatory phenotype of macrophages with protective features regarding APAP); 4. investigating therapeutic implications by blocking CCR2 and the CCR2 ligand CCL2 by innovative specific pharmacological inhibitors (we have administered the CCL2 inhibiting RNA-aptamer mNOX as well as a small molecular CCR2/CCR5 inhibitor cenicriviroc during progression and resolution); 5. translational approaches to the pathogenesis of human acute liver failure (by characterizing human liver samples by multi-color FACS and immunostaining, comprehensive comparisons to the mouse model data). Collectively, we identified the critical contribution of monocyte-derived macrophages on APAP-induced ALF and explored therapeutic implications for the treatment of acute liver failure in humans.
Publications
- Biomarker and Therapeutic Potential of CSF1 in Acute Liver Failure. Gastroenterology. 2015; 149(7):1675-8
Tacke F, Wynn TA
(See online at https://doi.org/10.1053/j.gastro.2015.10.024) - Chemokine (C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury. Hepatology 2016; 64:1667-1682
Mossanen JC, Krenkel O, Ergen C, Govaere O, Liepelt A, Puengel T, Heymann F, et al.
(See online at https://doi.org/10.1002/hep.28682) - CX3CR1 modulates the anti-inflammatory activity of hepatic dendritic cells in response to acute liver injury. Clin Sci (Lond) 2017; 131:2289-2301
Sutti S, Heymann F, Bruzzi S, Peusquens J, Trautwein C, Albano E, Tacke F
(See online at https://doi.org/10.1042/cs20171025) - Differential impact of the dual CCR2/CCR5 inhibitor cenicriviroc on migration of monocyte and lymphocyte subsets in acute liver injury. PLoS One 2017; 12:e0184694
Puengel T, Krenkel O, Kohlhepp M, Lefebvre E, Luedde T, Trautwein C, Tacke F
(See online at https://doi.org/10.1371/journal.pone.0184694) - Repair macrophages in acute liver failure. Gut. 2018; 67(2):202-203
Puengel T, Tacke F
(See online at https://doi.org/10.1136/gutjnl-2017-314245) - Myeloid cells in liver and bone marrow acquire a functionally distinct inflammatory phenotype during obesity-related steatohepatitis. Gut. 2020; 69(3):551-563
Krenkel O, Hundertmark J, Abdallah AT, Kohlhepp M, Puengel T, Roth T, Branco DPP, Mossanen JC, Luedde T, Trautwein C, Costa IG, Tacke F
(See online at https://doi.org/10.1136/gutjnl-2019-318382)
