Pharmacological inhibition of the chemokine C-C motif chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6C(+) macrophage infiltration in mice.
Macrophages constitute a major proinflammatory component during chronic liver diseases and are considered a key factor in promoting hepatic fibrosis. However, there is increasing evidence that distinct monocyte and macrophage subsets exert critical functions in regression from organ fibrosis as well. Experimental mouse models of fibrosis regression have identified "restorative" macrophages as Ly-6C (Ly6C, Gr1) low-expressing, monocyte-derived cells. We investigated molecular pathways balancing proinflammatory and restorative macrophages during fibrosis regression as well as pharmacologically augmenting beneficial macrophage functionality in fibrosis resolution. Therefore, we employed a Spiegelmer-based inhibitor of the chemokine, C-C motif chemokine ligand 2 (CCL2; monocyte chemoattractant protein 1), termed mNOX-E36, in the regression phase of two murine models of toxic (CCl4 ) and metabolic (methionine-choline-deficient diet) liver fibrosis. Although inflammation rapidly declined after cessation of injury, we observed a transient influx of Ly-6C(+) infiltrating monocytes (iMΦ), which are characterized by typical macrophage morphology, up-regulated expression of CCR2, and the pro-inflammatory cytokine, tumor necrosis factor (TNF), in injured liver. By inhibiting the early influx of Ly-6C(+) iMΦ by the CCL2 inhibitor, mNOX-E36, the intrahepatic macrophage equilibration shifted toward the "restorative" Ly-6C(-) subset of iMΦ. Consequently, fibrosis resolution was significantly accelerated upon mNOX-E36 administration in both models. Blocking transient recruitment of infiltrating Ly-6C(+) monocytes, but not direct effects of the inhibitor on the remaining macrophages, resulted in reduced intrahepatic levels of proinflammatory cytokines.


CONCLUSIONS
Transient CCL2-dependent recruitment of infiltrating Ly-6C(+) monocytes during fibrosis regression counteracts scar resolution by perpetuating inflammatory reactions through release of proinflammatory cytokines such as TNF. Pharmacological inhibition of Ly-6C(+) monocyte recruitment using the CCL2-inhibitor, mNOX-E36, accelerates regression from toxic and metabolic liver fibrosis in two independent experimental models.
Department of Medicine III, University Hospital Aachen, Aachen, Germany.
Christer
C
Baeck
Xiao
X
Wei
Matthias
M
Bartneck
Viktor
V
Fech
Felix
F
Heymann
Nikolaus
N
Gassler
Kanishka
K
Hittatiya
Dirk
D
Eulberg
Tom
T
Luedde
Christian
C
Trautwein
Frank
F
Tacke
D000818:Animals; D052157:Aptamers, Nucleotide / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000276:immunology; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D002908:Chronic Disease; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
D052157:Aptamers, Nucleotide; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; C528578:NOX-E36-3'PEG, mouse