Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair
Jeremy S. Duffield, Stuart J. Forbes, Christothea M. Constandinou, Spike Clay, Marina Partolina, Srilatha Vuthoori, Shengji Wu, Richard Lang, John P. Iredale
Jeremy S. Duffield, Stuart J. Forbes, Christothea M. Constandinou, Spike Clay, Marina Partolina, Srilatha Vuthoori, Shengji Wu, Richard Lang, John P. Iredale
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Article Immunology

Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair

Abstract

Macrophages perform both injury-inducing and repair-promoting tasks in different models of inflammation, leading to a model of macrophage function in which distinct patterns of activation have been proposed. We investigated macrophage function mechanistically in a reversible model of liver injury in which the injury and recovery phases are distinct. Carbon tetrachloride--–induced liver fibrosis revealed scar-associated macrophages that persisted throughout recovery. A transgenic mouse (CD11b-DTR) was generated in which macrophages could be selectively depleted. Macrophage depletion when liver fibrosis was advanced resulted in reduced scarring and fewer myofibroblasts. Macrophage depletion during recovery, by contrast, led to a failure of matrix degradation. These data provide the first clear evidence that functionally distinct subpopulations of macrophages exist in the same tissue and that these macrophages play critical roles in both the injury and recovery phases of inflammatory scarring.

Authors

Jeremy S. Duffield, Stuart J. Forbes, Christothea M. Constandinou, Spike Clay, Marina Partolina, Srilatha Vuthoori, Shengji Wu, Richard Lang, John P. Iredale

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The effect of DT treatment on SAMs in CD11b-DTR mouse liver at peak fibr...
The effect of DT treatment on SAMs in CD11b-DTR mouse liver at peak fibrosis and after 7 days of spontaneous recovery. (A–D) Photomicrographs (magnification, ×400) showing (A) macrophages (Mφ) associated with areas of scarring after 12 weeks of CCl4-induced injury; (B) absence of macrophages in an area of scarring at 12 weeks of CCl4 injury, following 5 days of macrophage depletion; (C) macrophages associated with resolving fibrotic band, at 7 days of recovery from CCl4 injury; and (D) absence of macrophages in scar following macrophage depletion during spontaneous recovery. (E and F) Area of macrophage in fibrotic bands (E) at peak fibrosis following treatment with i.v. PBS, i.p. DT or i.v. DT, or (F) after 7 days of spontaneous recovery after treatment with i.v. PBS, i.p. DT, or i.v. DT (**P < 0.01).