scispace - formally typeset
Search or ask a question
Author

Antonella Pellicoro

Other affiliations: Medical Research Council
Bio: Antonella Pellicoro is an academic researcher from University of Edinburgh. The author has contributed to research in topics: Fibrosis & Hepatic stellate cell. The author has an hindex of 12, co-authored 19 publications receiving 3217 citations. Previous affiliations of Antonella Pellicoro include Medical Research Council.

Papers
More filters
Journal ArticleDOI
TL;DR: This Review focuses on recent advances in liver fibrosis research as a paradigm for wound healing in solid organs and the role of the immune system in regulating and balancing this response.
Abstract: Fibrosis is a highly conserved and co-ordinated protective response to tissue injury. The interaction of multiple pathways, molecules and systems determines whether fibrosis is self-limiting and homeostatic, or whether it is uncontrolled and excessive. Immune cells have been identified as key players in this fibrotic cascade, with the capacity to exert either injury-inducing or repair-promoting effects. A multi-organ approach was recently suggested to identify the core and regulatory pathways in fibrosis, with the aim of integrating the wealth of information emerging from basic fibrosis research. In this Review, we focus on recent advances in liver fibrosis research as a paradigm for wound healing in solid organs and the role of the immune system in regulating and balancing this response.

985 citations

Journal ArticleDOI
TL;DR: The restorative macrophage phenotype was recapitulated in vitro by the phagocytosis of cellular debris with associated activation of the ERK signaling cascade, offering a therapeutic strategy to this orphan pathological process.
Abstract: Although macrophages are widely recognized to have a profibrotic role in inflammation, we have used a highly tractable CCl4-induced model of reversible hepatic fibrosis to identify and characterize the macrophage phenotype responsible for tissue remodeling: the hitherto elusive restorative macrophage. This CD11Bhi F4/80int Ly-6Clo macrophage subset was most abundant in livers during maximal fibrosis resolution and represented the principle matrix metalloproteinase (MMP) -expressing subset. Depletion of this population in CD11B promoter–diphtheria toxin receptor (CD11B-DTR) transgenic mice caused a failure of scar remodeling. Adoptive transfer and in situ labeling experiments showed that these restorative macrophages derive from recruited Ly-6Chi monocytes, a common origin with profibrotic Ly-6Chi macrophages, indicative of a phenotypic switch in vivo conferring proresolution properties. Microarray profiling of the Ly-6Clo subset, compared with Ly-6Chi macrophages, showed a phenotype outside the M1/M2 classification, with increased expression of MMPs, growth factors, and phagocytosis-related genes, including Mmp9, Mmp12, insulin-like growth factor 1 (Igf1), and Glycoprotein (transmembrane) nmb (Gpnmb). Confocal microscopy confirmed the postphagocytic nature of restorative macrophages. Furthermore, the restorative macrophage phenotype was recapitulated in vitro by the phagocytosis of cellular debris with associated activation of the ERK signaling cascade. Critically, induced phagocytic behavior in vivo, through administration of liposomes, increased restorative macrophage number and accelerated fibrosis resolution, offering a therapeutic strategy to this orphan pathological process.

744 citations

Journal ArticleDOI
TL;DR: Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the αv integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis.
Abstract: Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of Pdgfrb (Pdgfrb-Cre) inactivates loxP-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding α(v) integrin subunit because various α(v)-containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride-induced hepatic fibrosis, whereas global loss of β₃, β₅ or β₆ integrins or conditional loss of β₈ integrins in HSCs did not. We also found that Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the α(v) integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of α(v)-containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all α(v) integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.

686 citations

Journal ArticleDOI
TL;DR: It is found that during biliary regeneration, expression of Jagged 1 by myofibroblasts promoted Notch signaling in HPCs and thus their biliary specification to cholangiocytes and thus the promotion of their specification to hepatocytes.
Abstract: During chronic injury a population of bipotent hepatic progenitor cells (HPCs) become activated to regenerate both cholangiocytes and hepatocytes. Here we show in human diseased liver and mouse models of the ductular reaction that Notch and Wnt signaling direct specification of HPCs via their interactions with activated myofibroblasts or macrophages. In particular, we found that during biliary regeneration, expression of Jagged 1 (a Notch ligand) by myofibroblasts promoted Notch signaling in HPCs and thus their biliary specification to cholangiocytes. Alternatively, during hepatocyte regeneration, macrophage engulfment of hepatocyte debris induced Wnt3a expression. This resulted in canonical Wnt signaling in nearby HPCs, thus maintaining expression of Numb (a cell fate determinant) within these cells and the promotion of their specification to hepatocytes. By these two pathways adult parenchymal regeneration during chronic liver injury is promoted.

643 citations

Journal ArticleDOI
TL;DR: It is shown that elastin turnover in liver injury and fibrosis is regulated by macrophages via Mmp-12 expression, activity and ratio to its inhibitor Timp-1, which leads to accumulation ofElastin in the fibrotic scars.
Abstract: Liver fibrosis, and its end stage cirrhosis are a major cause of morbidity and mortality and therapeutic options are limited. However, the traditional view of liver disease as an irreversible process is obsolete and it is now evident that the development of liver fibrosis is a dynamic and potentially bidirectional process. Spontaneous resolution of scarring is seen in animal models of liver fibrosis and in human trials in which the stimuli responsible for chronic or repeated hepatic inflammation is successfully removed. Key players in the process are hepatic stellate cells, macrophages, MMPs and their inhibitors Timps. It is also evident that in advanced fibrotic liver disease, specific histological features define what is currently described as "irreversible" fibrosis. This includes the development of paucicellular scars enriched in extensively cross-linked matrix components, such as fibrillar collagen and elastin. Our recent work has focused on the role of macrophage metalloelastase (MMP-12) in the turnover of elastin in reversible and irreversible models of fibrosis. We have shown that elastin turnover in liver injury and fibrosis is regulated by macrophages via Mmp-12 expression, activity and ratio to its inhibitor Timp-1. Failure of elastin degradation, together with increased deposition leads to accumulation of elastin in the fibrotic scars.

189 citations


Cited by
More filters
Journal ArticleDOI
25 Apr 2013-Nature
TL;DR: This Review discusses how macrophage regulate normal physiology and development, and provides several examples of their pathophysiological roles in disease, and defines the ‘hallmarks’ of macrophages according to the states that they adopt during the performance of their various roles.
Abstract: Macrophages, the most plastic cells of the haematopoietic system, are found in all tissues and show great functional diversity. They have roles in development, homeostasis, tissue repair and immunity. Although tissue macrophages are anatomically distinct from one another, and have different transcriptional profiles and functional capabilities, they are all required for the maintenance of homeostasis. However, these reparative and homeostatic functions can be subverted by chronic insults, resulting in a causal association of macrophages with disease states. In this Review, we discuss how macrophages regulate normal physiology and development, and provide several examples of their pathophysiological roles in disease. We define the 'hallmarks' of macrophages according to the states that they adopt during the performance of their various roles, taking into account new insights into the diversity of their lineages, identities and regulation. It is essential to understand this diversity because macrophages have emerged as important therapeutic targets in many human diseases.

3,368 citations

Journal ArticleDOI
TL;DR: The extracellular matrix is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands, and its regulation contributes to several pathological conditions, such as fibrosis and invasive cancer.
Abstract: The extracellular matrix (ECM) is a highly dynamic structure that is present in all tissues and continuously undergoes controlled remodelling. This process involves quantitative and qualitative changes in the ECM, mediated by specific enzymes that are responsible for ECM degradation, such as metalloproteinases. The ECM interacts with cells to regulate diverse functions, including proliferation, migration and differentiation. ECM remodelling is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands. Dysregulation of ECM composition, structure, stiffness and abundance contributes to several pathological conditions, such as fibrosis and invasive cancer. A better understanding of how the ECM regulates organ structure and function and of how ECM remodelling affects disease progression will contribute to the development of new therapeutics.

2,854 citations

Journal ArticleDOI
15 Mar 2016-Immunity
TL;DR: This review discusses the mechanisms that instruct macrophages to adopt pro-inflammatory, pro-wound-healing,pro-fibrotic, anti- inflammatory, anti -fib rotic, Pro-resolving, and tissue-regenerating phenotypes after injury, and highlights how some of these mechanisms and macrophage activation states could be exploited therapeutically.

2,284 citations

Journal ArticleDOI
TL;DR: Using scRNA-seq analysis, Bhattacharya and colleagues identify a subset of profibrotic lung macrophages that have a gene expression signature intermediate between those of monocytes and alveolar macrophage.
Abstract: Tissue fibrosis is a major cause of mortality that results from the deposition of matrix proteins by an activated mesenchyme. Macrophages accumulate in fibrosis, but the role of specific subgroups in supporting fibrogenesis has not been investigated in vivo. Here, we used single-cell RNA sequencing (scRNA-seq) to characterize the heterogeneity of macrophages in bleomycin-induced lung fibrosis in mice. A novel computational framework for the annotation of scRNA-seq by reference to bulk transcriptomes (SingleR) enabled the subclustering of macrophages and revealed a disease-associated subgroup with a transitional gene expression profile intermediate between monocyte-derived and alveolar macrophages. These CX3CR1+SiglecF+ transitional macrophages localized to the fibrotic niche and had a profibrotic effect in vivo. Human orthologs of genes expressed by the transitional macrophages were upregulated in samples from patients with idiopathic pulmonary fibrosis. Thus, we have identified a pathological subgroup of transitional macrophages that are required for the fibrotic response to injury.

1,790 citations

Journal Article
TL;DR: Schulz et al. as discussed by the authors investigated whether adult macrophages all share a common developmental origin and found that a population of yolk-sac-derived, tissue-resident macophages was able to develop and persist in adult mice in the absence of hematopoietic stem cells.
Abstract: Macrophage Development Rewritten Macrophages provide protection against a wide variety of infections and critically shape the inflammatory environment in many tissues. These cells come in many flavors, as determined by differences in gene expression, cell surface phenotype and specific function. Schulz et al. (p. 86, published online 22 March) investigated whether adult macrophages all share a common developmental origin. Immune cells, including most macrophages, are widely thought to arise from hematopoietic stem cells (HSCs), which require the transcription factor Myb for their development. Analysis of Myb-deficient mice revealed that a population of yolk-sac–derived, tissue-resident macrophages was able to develop and persist in adult mice in the absence of HSCs. Importantly, yolk sac–derived macrophages also contributed substantially to the tissue macrophage pool even when HSCs were present. In mice, a population of tissue-resident macrophages arises independently of bone marrow–derived stem cells. Macrophages and dendritic cells (DCs) are key components of cellular immunity and are thought to originate and renew from hematopoietic stem cells (HSCs). However, some macrophages develop in the embryo before the appearance of definitive HSCs. We thus reinvestigated macrophage development. We found that the transcription factor Myb was required for development of HSCs and all CD11bhigh monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80bright macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia—cell populations that all can persist in adult mice independently of HSCs. These results define a lineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny.

1,673 citations