Ly6C high monocytes and their macrophage descendants regulate neutrophil function and clearance in acetaminophen-induced liver injury. Mus musculus

Monocyte-derived macrophages 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 necro-inflammatory and resolution phases of AILI. We utilized MC-21 anti mouse CCR2 to induce the ablation of circulating Ly6Chi monocytes. RNA sequencing-based profiling of neutrophils from Ly6Chi monocyte-deficient(MC-21 treated mice) versus normal livers (PBS-treated mice) revealed 449 genes that were differentially expressed with at least two-fold change (p ≤ 0.05). Nutrophils from monocyte-ablated livers exhibited decreased expression of NADPH Oxidase 2. Moreover, in the absence of Ly6Chi monocytes, neutrophils exhibited an altered transcriptomic profile associated with reduced innate activity concomitantly with increased cell survival.Collectively, our findings reveal that liver-infiltrating Ly6Chi monocytes regulating neutrophil activity and survival following AILI. Overall design: Neutrophils (defined as Ly6G+CD11b+Ly6Clo cells) were sorted at 24h following AILI from normal livers (n=4) or livers that are deficient for Ly6Chi infiltrating monocytes (n=3). RNA-seq based transcriptomicn profiling was performed to deliniate the effect of monocyte deficiency on nuetrophil activity and survival.