Table 2. Strategies for therapeutic targeting of hepatic macrophages (derived from experimental models of chronic liver injury).

Target	Possible approach (selected from experimental models)	Reference(s)
Dampening Kupffer cell activation by influencing the gut–liver axis	• restoration of the normal microbiome, by application of probiotics, antibiotics or fecal microbiota transfer;	29,115,117,118
	• sequestering of deoxycholic acid (or other bile acids associated formation oxidative stress and DNA damage);
	• application of compounds that lead to elevated tightness of the intestinal barrier.
Inhibition of (Ly-6C+) inflammatory monocyte recruitment to the liver	• pharmacological antagonism of CCL2 (MCP-1), e.g., by RNA aptamer molecules;	103,120
	• pharmacological inhibition of CCR2 and/or of other related chemokine receptors like CCR1/CCR5 (e.g., cenicriviroc).
Modulatinghepatic macrophage polarization and function	• nanoparticles influencing hepatic macrophage polarization;	123,126,128,129,131,132
	• Delivery of “polarizing” drugs (e.g., dexamethasone) to hepatic macrophages;
	• Neutralization of inflammatory effector cytokines like TNF and IL-1;
	• Inhibition of the pro-inflammatory mediator Galectin-3.
Augmentation of restorative hepatic macrophages	• Application of IL-4 to force local proliferation of tissue-remodeling macrophages;	20,120,135,136
	• Autologous cell transfer of in vitro matured and polarized macrophages or of hematopoietic precursors;
	• Inhibition of inflammatory monocyte influx during the regression of fibrosis;
	• Injecting apoptotic cells or PS-containing liposomes to accelerate the differentiation to Ly-6Clow macrophages.