Abstract
Monocyte-derived macrophages (MoMF) play a pivotal role in the resolution of acetaminophen-induced liver injury (AILI). Timely termination of neutrophil activity and their clearance are essential for liver regeneration following injury. Here, we show that infiltrating Ly6Chi monocytes, their macrophage descendants, and neutrophils spatially and temporally overlap in the centrilobular necrotic areas during the necroinflammatory and resolution phases of AILI. At the necroinflammatory phase, inducible ablation of circulating Ly6Chi monocytes resulted in reduced numbers and fractions of reactive oxygen species (ROS)-producing neutrophils. In alignment with this, neutrophils sorted from monocyte-deficient livers exhibited reduced expression of NADPH oxidase 2. Moreover, human CD14+ monocytes stimulated with lipopolysaccharide or hepatocyte apoptotic bodies directly induced ROS production by cocultured neutrophils. RNA-seq-based transcriptome profiling of neutrophils from Ly6Chi monocyte-deficient versus normal livers revealed 449 genes that were differentially expressed with at least twofold change (p ≤ 0.05). In the absence of Ly6Chi monocytes, neutrophils displayed gene expression alterations associated with decreased innate immune activity and increased cell survival. At the early resolution phase, Ly6Chi monocytes differentiated into ephemeral Ly6Clo MoMF and their absence resulted in significant accumulation of late apoptotic neutrophils. Further gene expression analysis revealed the induced expression of a specific repertoire of bridging molecules and receptors involved with apoptotic cell clearance during the transition from Ly6Chi monocytes to MoMF. Collectively, our findings establish a phase-dependent task division between liver-infiltrating Ly6Chi monocytes and their MoMF descendants with the former regulating innate immune functions and cell survival of neutrophils and the later neutrophil clearance.
Highlights
One of the most peculiar characteristics of the liver is the regenerative process that occurs in response to damage and/or injury
Acetaminophen-Induced Liver Injury is associated with massive liver infiltration of monocytes and neutrophils [6, 22, 35, 37]
Immunofluorescent staining of Cx3cr1gfp/+ liver sections revealed that Ly6G+ neutrophils and CX3CR1-GFP+ monocyte-derived cells colocalize within the centrilobular necrotic areas at 24 and 48 h following APAP-induced liver injury (AILI) (Figure 1C, Movie S1 in Supplementary Material)
Summary
One of the most peculiar characteristics of the liver is the regenerative process that occurs in response to damage and/or injury. Key players of this healing reaction are recruited monocytes and macrophages that undergo marked phenotypic and functional changes that, which license them to promote the initiation, maintenance, and resolution phases of tissue repair [1]. In a model of reversible hepatic fibrosis, these monocytes advance fibrogenesis [7], yet at the resolution phase, the same cells give rise to distinct Ly6Clo prorestorative macrophages that actively promote liver regeneration [5, 8]. Similar functional dichotomy was reported in the healing of other tissue-specific injuries such as heart [17], skeletal muscle [18], spinal cord [19], retina [20], and sterile wounds [21]
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