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.

The microRNA miR-504 targets TP53 mRNA encoding the p53 tumor suppressor. miR-504 resides within the fibroblast growth factor 13 (FGF13) gene, which is overexpressed in various cancers. We report that the FGF13 locus, comprising FGF13 and miR-504, is transcriptionally repressed by p53, defining an additional negative feedback loop in the p53 network. Furthermore, we show that FGF13 1A is a nucleolar protein that represses ribosomal RNA transcription and attenuates protein synthesis. Importantly, in cancer cells expressing high levels of FGF13, the depletion of FGF13 elicits increased proteostasis stress, associated with the accumulation of reactive oxygen species and apoptosis. Notably, stepwise neoplastic transformation is accompanied by a gradual increase in FGF13 expression and increased dependence on FGF13 for survival ("nononcogene addiction"). Moreover, FGF13 overexpression enables cells to cope more effectively with the stress elicited by oncogenic Ras protein. We propose that, in cells in which activated oncogenes drive excessive protein synthesis, FGF13 may favor survival by maintaining translation rates at a level compatible with the protein qualitycontrol capacity of the cell. Thus, FGF13 may serve as an enabler, allowing cancer cells to evade proteostasis stress triggered by oncogene activation.proteostasis | p53 | miR-504 | FGF13 | ribosomal biogenesis

Ly6Chi monocyte tissue infiltrates play important roles in mediating local inflammation, bacterial elimination and resolution during sepsis and inflammatory bowel disease (IBD). Yet, the immunoregulatory pathways dictating their activity remain poorly understood. COMMD family proteins are emerging as key regulators of signaling and protein trafficking events during inflammation, but the specific role of COMMD10 in governing Ly6Chi monocyte-driven inflammation is unknown. Here we report that COMMD10 curbs canonical and non-canonical inflammasome activity in Ly6Chi monocytes in a model of LPS-induced systemic inflammation. Accordingly, its deficiency in myeloid cells, but not in tissue resident macrophages, resulted in increased Ly6Chi monocyte liver and colonic infiltrates, elevated systemic cytokine storm, increased activation of caspase-1 and-11 in the liver and colon, and augmented IL-1β production systemically and specifically in LPS-challenged circulating Ly6Chi monocytes. These inflammatory manifestations were accompanied by impaired intestinal barrier function with ensuing bacterial dissemination to the mesenteric lymph nodes and liver leading to increased mortality. The increased inflammasome activity and intestinal barrier leakage were ameliorated by the inducible ablation of COMMD10-deficient Ly6Chi monocytes. In consistence with these results, COMMD10-deficiency in Ly6Chi monocytes, but not in intestinal-resident lamina propria macrophages, led to increased IL-1β production and aggravated colonic inflammation in a model of DSS-induced colitis. Finally, COMMD10 expression was reduced in Ly6Chi monocytes and their corresponding human CD14hi monocytes sorted from mice subjected to DSS-induced colitis or from IBD patients, respectively. Collectively, these results highlight COMMD10 as a negative regulator of Ly6Chi monocyte inflammasome activity during systemic inflammation and IBD.