Inhibition of intrahepatic monocyte recruitment by Cenicriviroc and extracellular matrix degradation by MMP1 synergistically attenuate liver inflammation and fibrogenesis in vivo
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The chemokine (CCL)-chemokine receptor (CCR2) interaction, importantly CCL2-CCR2, involved in the intrahepatic recruitment of monocytes upon liver injury promotes liver fibrosis. CCL2-CCR2 antagonism using Cenicriviroc (CVC) showed promising results in several preclinical studies. Unfortunately, CVC failed in phase III clinical trials due to lack of efficacy to treat liver fibrosis. Lack of efficacy could be attributed to the fact that macrophages are also involved in disease resolution by secreting matrix metalloproteinases (MMPs) to degrade extracellular matrix (ECM), thereby inhibiting hepatic stellate cells (HSCs) activation. HSCs are the key pathogenic cell types in liver fibrosis that secrete excessive amounts of ECM causing liver stiffening and liver dysfunction. Knowing the detrimental role of intrahepatic monocyte recruitment, ECM, and HSCs activation during liver injury, we hypothesize that combining CVC and MMP (MMP1) could reverse liver fibrosis. We evaluated the effects of CVC, MMP1 and CVC + MMP1 in vitro and in vivo in CCl 4 -induced liver injury mouse model. We observed that CVC + MMP1 inhibited macrophage migration, and TGF-β induced collagen-I expression in fibroblasts in vitro. In vivo, MMP1 + CVC significantly inhibited normalized liver weights, and improved liver function without any adverse effects. Moreover, MMP1 + CVC inhibited monocyte infiltration and liver inflammation as confirmed by F4/80 and CD11b staining, and TNFα gene expression. MMP1 + CVC also ameliorated liver fibrogenesis via inhibiting HSCs activation as assessed by collagen-I staining and collagen-I and α-SMA mRNA expression. In conclusion, we demonstrated that a combination therapeutic approach by combining CVC and MMP1 to inhibit intrahepatic monocyte recruitment and increasing collagen degradation respectively ameliorate liver inflammation and fibrosis.
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Kupffer cells initiate and regulate the hepatic immune niche by producing CCL2 to recruit CCR2+ monocytes and secreting IL-1β/TNF-α that shape recruited macrophage polarization following injury.
“Resident KCs initiate and regulate the hepatic immune niche by producing C-C motif chemokine ligand 2 (CCL2) to recruit C-C motif chemokine receptor 2 (CCR2)+ monocytes and secreting IL-1β/TNF-α that shape recruited macrophages polarization following injury (27–29).”
From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [28]
The Introduction and Figure 1 description (page not provided) state that Kupffer cells secrete CCL2, which recruits CCR2-expressing monocytes after liver injury. They do not say that Kupffer cells secrete IL-1β or TNF-α to shape the polarization of recruited macrophages; searches for those terms and polarization did not establish that part of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCombining CVC with MMP1 synergistically reduced inflammation and fibrosis in preclinical work.
“Preclinical work by Geervliet et al. showed that combining CVC with matrix metalloproteinase 1 (MMP1, an enzyme that degrades ECM) synergistically reduced inflammation and fibrosis, combining inhibition of new recruitment with promotion of matrix degradation (28).”
From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [28]
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- Authors
- Geervliet, E., Karkdijk, E., & Bansal, R.
- Affiliations
- University of Twente (NL)
- Corresponding author
- Bansal, Ruchi
- Venue
- Scientific Reports
- Published
- 2024-07-23
- Volume
- 14
- Issue
- 1
- Pages
- 16897-16897
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC11266417
- OpenAlex
- W4400921676
- Cited by
- 15
- References
- 46
- Citations by year
- 2026: 10 · 2025: 5
- FWCI
- 3.93
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Scientific Reports (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- University of Twente Research Information (submittedVersion, cc-by-nc-nd)
- Funders
- University of Twente (Bansal Start-up)
- European Association for the Study of the Liver (Juan Rodes Ph.D. Student Fellowship)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- cenicriviroc, MMP-1, liver fibrosis, liver inflammation, monocyte recruitment, hepatic stellate cell activation, extracellular matrix degradation, macrophage migration, combination therapy, carbon tetrachloride-induced liver injury, collagen degradation, TGF-beta
- MeSH terms
- Animals, Carbon Tetrachloride, Cell Movement, Disease Models, Animal, Drug Synergism, Extracellular Matrix, Humans, Imidazoles, Liver, Liver Cirrhosis, Macrophages, Male, Mice, Inbred C57BL, Monocytes, Sulfoxides, Matrix Metalloproteinase 1, Mice, Hepatic Stellate Cells
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