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Background & Aims Kupffer cells (KCs), the resident tissue macrophages of the liver, play a crucial role in the clearance of pathogens and other particulate materials that reach the systemic circulation. Recent studies have identified KCs as a yolk sac-derived resident macrophage population that is replenished independently of monocytes in the steady state. Although it is now established that following local tissue injury, bone marrow derived monocytes may infiltrate the tissue and differentiate into macrophages, the extent to which newly differentiated macrophages functionally resemble the KCs they have replaced has not been extensively studied. Methods We studied the two populations of KCs using intravital microscopy, morphometric analysis and gene expression profiling. An ion homeostasis gene signature, including genes associated with scavenger receptor function and extracellular matrix deposition, allowed discrimination between these two KC sub-types. Results Bone marrow derived “KCs” accumulating as a result of genotoxic injury, resemble but are not identical to their yolk sac counterparts. Reflecting the differential expression of scavenger receptors, yolk sac-derived KCs were more effective at accumulating acetylated low density lipoprotein, whereas surprisingly, they were poorer than bone marrow-derived KCs when assessed for uptake of a range of bacterial pathogens. The two KC populations were almost indistinguishable in regard to i) response to lipopolysaccharide challenge, ii) phagocytosis of effete red blood cells and iii) their ability to contain infection and direct granuloma formation against Leishmania donovani , a KC-tropic intracellular parasite. Conclusions Bone marrow-derived KCs differentiate locally to resemble yolk sac-derived KC in most but not all respects, with implications for models of infectious diseases, liver injury and bone marrow transplantation. In addition, the gene signature we describe adds to the tools available for distinguishing KC subpopulations based on their ontology. Lay summary Liver macrophages play a major role in the control of infections in the liver and in the pathology associated with chronic liver diseases. It was recently shown that liver macrophages can have two different origins, however, the extent to which these populations are functionally distinct remains to be fully addressed. Our study demonstrates that whilst liver macrophages share many features in common, regardless of their origin, some subtle differences in function exist. Data repository Gene expression data are available from the European Bioinformatics Institute ArrayExpress data repository (accession number E-MTAB-4954). [ABSTRACT FROM AUTHOR]

Abstract: Ingenol-3-angelate is a new local chemotherapeutic agent in clinical trails that induces primary necrosis of tumour cells and transient local inflammation. Here we show that cure of subcutaneous tumours with ingenol-3-angelate (PEP005) resulted in the generation of anti-cancer CD8 T cells that could regress metastases. Furthermore, PEP005-mediated cure synergized with several CD8 T cell-based immunotherapies to regress further distant metastases. PEP005 was shown to have adjuvant properties, being able to upregulate CD80 and CD86 expression on dendritic cells in vivo, and to promote CD8 T cell induction when co-delivered with a protein antigen. PEP005 thus emerges as a unique local chemotherapeutic immunostimulatory debulking agent that could be used in conjunction with immunotherapies to promote regression of metastases. [Copyright &y& Elsevier]