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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Figure 1

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The relationship between SAMs, collagenous bands, and HSCs during CCl4 i...
The relationship between SAMs, collagenous bands, and HSCs during CCl4 injury and recovery in the Sprague-Dawley rat. (A) Sirius red staining (magnification, ×100) of liver for collagenous bands at 4, 6, and 12 weeks of disease, and following 28 days of recovery after 12 weeks of injury. (B) ED-1 macrophages (magnification, ×100) are associated with scar tissue after 4, 6, and 12 weeks of disease, and following 28 days of recovery after 12 weeks of injury. (C) Graph of SAMs and α-SMA–positive HSCs at different stages of recovery from CCl4-induced fibrosis (4 weeks intoxication). Note the rapid decline in HSCs in the early phase of recovery.