Sorted in reverse chronological order.

Click on the title (in blue) to be linked to the original article on the journal website.

 

Yang Q, Shi Y, He J, Chen Z. The evolving story of macrophages in acute liver failure.
Immunology Letters [Internet]. 2012 Jul [cited 2012 Jul 27];(0).

ABSTRACT: Acute liver failure (ALF) remains a worldwide problem. The innate immune system acts as an important regulator of ALF. Kupffer cells (KCs), the resident macrophages in liver, play a key role in liver innate immune response. Recent researches have shown that macrophages display a remarkable plasticity and can differentiate into functionally diverse subsets. However, the dynamic polarized phenotypes and functional status of macrophages in different stage of ALF are not clear. In this paper, we present a review of evidence that KCs play a significant role in the pathogenesis of ALF, including the phenotype and functions of macrophages, signaling pathways involved in macrophage functional status and cell-crosstalks of KCs with other immune cells. More information on macrophages will promote a better understanding of the cellular molecular mechanisms of ALF and provide new insights for the development of therapeutic targets for ALF.


Li J, Hsu H-C, Mountz JD.Managing Macrophages in Rheumatoid Arthritis by Reform or Removal.
Current Rheumatology Reports [Internet]. 2012 Aug 2 [cited 2012 Aug 3];

ABSTRACT: Macrophages play a central role in the pathogenesis of rheumatoid arthritis (RA). There is an imbalance of inflammatory and antiinflammatory macrophages in RA synovium. Although the polarization and heterogeneity of macrophages in RA have not been fully uncovered, the identity of macrophages in RA can potentially be defined by their products, including the co-stimulatory molecules, scavenger receptors, different cytokines/chemokines and receptors, and transcription factors. In the last decade, efforts to understand the polarization, apoptosis regulation, and novel signaling pathways in macrophages, as well as how distinct activated macrophages influence disease progression, have led to strategies that target macrophages with varied specificity and selectivity. Major targets that are related to macrophage development and apoptosis include TNF-α, IL-1, IL-6, GM-CSF, M-CSF, death receptor 5 (DR5), Fas, and others, as listed in Table 1. Combined data from clinical, preclinical, and animal studies of inhibitors of these targets have provided valuable insights into their roles in the disease progression and, subsequently, have led to the evolving therapeutic paradigms in RA. In this review, we propose that reestablishment of macrophage equilibrium by inhibiting the development of, and/or eliminating, the proinflammatory macrophages will be an effective therapeutic approach for RA and other autoimmune diseases. Table 1 Novel macrophage-related therapeutic agents for rheumatoid diseases Agent Mechanisms Development phase Reference Antihuman DR5 antibody, TRA-8(CS-1008) Induces apoptosis of targeted cells Preclinical [27••] Tumor necrosis factor-converting enzyme (TACE) inhibitors, TMI-005 and BMS-561392 Inhibits the release of soluble TNF from its membrane-bound precursor Clinical Phase II [51] GM-CSF and GM-CSF receptor antibodies Blocks the binding of GM-CSF to its receptor and downstream signaling Clinical Phase II [3, 11••] JAK inhibitor, Tofacitinib and Ruxolitinib Abrogated TNF-induced STAT1 activation and expression of genes encoding inflammatory chemokines Clinical Phase III [12] Tyrosine kinase inhibitor, Imatinib and mastinib Inhibits tyrosine kinases, including platelet-derived growth factor receptor (PDGFR), Kit, and Fms related kinases Clinical Phase II-III [52, 53] Anti-IL-12/IL-23 monoclonal antibody, ustekinumab Blocking binding of IL-12/23 to their receptors and the downstream signaling Approved for psoriasis and psoriatic arthritis [54] Clodronate liposomes Deplete synovial macrophages by intraarticular administration Open study in patients who were scheduled for knee joint replacement [49].


Tabas I. Macrophage death and defective inflammation resolution in atherosclerosis.
Nature Reviews Immunology. 2009 Dec 4;10(1):36–46.

ABSTRACT: A key event in atherosclerosis is a maladaptive inflammatory response to subendothelial lipoproteins. A crucial aspect of this response is a failure to resolve inflammation, which normally involves the suppression of inflammatory cell influx, effective clearance of apoptotic cells and promotion of inflammatory cell egress. Defects in these processes promote the progression of atherosclerotic lesions into dangerous plaques, which can trigger atherothrombotic vascular disease, the leading cause of death in industrialized societies. In this Review I provide an overview of these concepts, with a focus on macrophage death and defective apoptotic cell clearance, and discuss new therapeutic strategies designed to boost inflammation resolution in atherosclerosis.


Liu J, Sun Y, Drubin DG, Oster GF. The Mechanochemistry of Endocytosis.
PLoS Biol. 2009;7(9):e1000204.

ABSTRACT: An integrated theoretical model reveals how the chemical and the mechanical aspects of endocytosis are coordinated coherently in yeast cells, driving progression through the endocytic pathway and ensuring efficient vesicle scission in vivo.


Liu J, Sun Y, Drubin DG, Oster GF. The Mechanochemistry of Endocytosis.
PLoS Biol. 2009;7(9):e1000204.

ABSTRACT: An integrated theoretical model reveals how the chemical and the mechanical aspects of endocytosis are coordinated coherently in yeast cells, driving progression through the endocytic pathway and ensuring efficient vesicle scission in vivo.


Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation.
Nature Reviews Immunology. 2008 Dec 1;8(12):958–69.

ABSTRACT: Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities — host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other ‘shades’ of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.


Schett G. Cells of the synovium in rheumatoid arthritis. Osteoclasts.
Arthritis Research & Therapy. 2007 Feb 15;9(1):203.

ABSTRACT: Osteoclasts are multinucleated cells of hematopoietic origin and are the primary bone resorbing cells. Numerous osteoclasts are found within the synovial tissue at sites adjacent to bone, creating resorption pits and local bone destruction. They are equipped with specific enzymes and a proton pump that enable them to degrade bone matrix and solubilize calcium, respectively. The synovial tissue of inflamed joints has a particularly high potential to accumulate osteoclasts because it harbors monocytes/macrophages, which function as osteoclast precursors, as well as cells that provide the specific molecular signals that drive osteoclast formation. Osteoclasts thus represent a link between joint inflammation and structural damage since they resorb mineralized tissue adjacent to the joint and destroy the joint architecture.


Lutzky V, Hannawi S, Thomas R. Cells of the synovium in rheumatoid arthritis. Dendritic cells.
Arthritis Research & Therapy. 2007 Sep 7;9(4):219.

ABSTRACT: Dendritic cells are the major antigen-presenting and antigen-priming cells of the immune system. We review the antigen-presenting and proinflammatory roles played by dendritic cells in the initiation of rheumatoid arthritis (RA) and atherosclerosis, which complicates RA. Various signals that promote the activation of NF-κB and the secretion of TNF and IL-1 drive the maturation of dendritic cells to prime self-specific responses, and drive the perpetuation of synovial inflammation. These signals may include genetic factors, infection, cigarette smoking, immunostimulatory DNA and oxidized low-density lipoprotein, with major involvement of autoantibodies. We propose that the pathogenesis of RA and atherosclerosis is intimately linked, with the vascular disease of RA driven by similar and simultaneous triggers to NF-κB.


Kinne RW, Stuhlmüller B, Burmester G-R. Cells of the synovium in rheumatoid arthritis. Macrophages.
Arthritis Research & Therapy. 2007 Dec 21;9(6):224.

ABSTRACT: The multitude and abundance of macrophage-derived mediators in rheumatoid arthritis and their paracrine/autocrine effects identify macrophages as local and systemic amplifiers of disease. Although uncovering the etiology of rheumatoid arthritis remains the ultimate means to silence the pathogenetic process, efforts in understanding how activated macrophages influence disease have led to optimization strategies to selectively target macrophages by agents tailored to specific features of macrophage activation. This approach has two advantages: (a) striking the cell population that mediates/amplifies most of the irreversible tissue destruction and (b) sparing other cells that have no (or only marginal) effects on joint damage.


Plüddemann A, Mukhopadhyay S, Gordon S. The Interaction of Macrophage Receptors with Bacterial Ligands.
Expert Reviews in Molecular Medicine. 2006;8(28):1–25.

ABSTRACT: Innate immune receptors play a key role in the early recognition of invading bacterial pathogens and initiate the crucial innate immune response. The diverse macrophage receptors recognise Gram-positive and Gram-negative bacteria via conserved structures on the bacterial surface and facilitate phagocytosis and/or signalling, providing the trigger for the adaptive immune response. These receptors include scavenger receptors, C-type lectins, integrins, Toll-like receptors and siglecs. The bacterial ligands generally recognised by these receptors range from lipopolysaccharides on Gram-negative bacteria to peptidoglycan and lipoteichoic acid on Gram-positive bacteria. However, emerging evidence indicates that bacterial proteins are also important ligands; for example, surface proteins from Neisseria meningitidis have been shown to be ligands for class A scavenger receptors. In addition, a group of cytosolic receptors, the NBS-LRR proteins, have been implicated in recognition of bacterial breakdown products. It is becoming increasingly apparent that macrophage receptors can act in conjunction with one another to deliver an appropriate response.


Stout RD, Suttles J. Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age‐associated microenvironmental changes.
Immunological Reviews. 2005 Jun 1;205(1):60–71.

ABSTRACT: The macrophage lineage displays extreme functional and phenotypic heterogeneity, which appears to be because, in large part, of the ability of macrophages to functionally adapt to changes in their tissue microenvironment. This functional plasticity of macrophages plays a critical role in their ability to respond to tissue damage and/or infection and to contribute to clearance of damaged tissue and invading microorganisms, to recruitment of the adaptive immune system, and to resolution of the wound and of the immune response. Evidence has accumulated that environmental influences, such as stromal function and imbalances in hormones and cytokines, contribute significantly to the dysfunction of the adaptive immune system. The innate immune system also appears to be dysfunctional in aged animals and humans. In this review, the hypothesis is presented and discussed that the observed age-associated ‘dysfunction’ of macrophages is the result of their functional adaptation to the age-associated changes in tissue environments. The resultant loss of orchestration of the manifold functional capabilities of macrophages would undermine the efficacy of both the innate and adaptive immune systems. The macrophages appear to maintain functional plasticity during this dysregulation, making them a prime target of cytokine therapy that could enhance both innate and adaptive immune systems.


Ross FP, Teitelbaum SL. αvβ3 and macrophage colony‐stimulating factor: partners in osteoclast biology.
Immunological Reviews. 2005 Dec 1;208(1):88–105.

ABSTRACT: Osteoclasts, the sole bone-resorbing cells, arise by fusion and differentiation of monocyte/macrophage precursors. Matrix degradation requires adhesion of the osteoclast to bone, an integrin αvβ3-mediated event that also stimulates signals which polarize the cell and secrete resorptive molecules such as hydrochloric acid and acidic proteases. Two cytokines are necessary and sufficient for osteoclastogenesis, receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), both produced by mesenchymal cells in the bone marrow environment. M-CSF promotes survival and proliferation of osteoclast precursors. It also contributes to their differentiation and regulates the cytoskeletal changes that accompany bone resorption. Binding of M-CSF to c-Fms, its receptor, recruits adapter proteins and cytosolic kinases, thereby activating a variety of intracellular signals. We herein review how αvβ3 and M-CSF, alone and in concert, impact production, survival, and function of the osteoclast, thereby controlling skeletal mass. Signals from αvβ3 and/or c-Fms activate Syk and Vav3, originally defined by their function in lymphoid cells. Genetic depletion of either protein generates a strong bone phenotype, underscoring the promise of osteoimmunobiology.


Gordon S, Taylor PR. Monocyte and macrophage heterogeneity.
Nature Reviews Immunology. 2005 Dec 1;5(12):953–64.

ABSTRACT: Heterogeneity of the macrophage lineage has long been recognized and, in part, is a result of the specialization of tissue macrophages in particular microenvironments. Circulating monocytes give rise to mature macrophages and are also heterogeneous themselves, although the physiological relevance of this is not completely understood. However, as we discuss here, recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues. These advances in our understanding have implications for the development of therapeutic strategies that are targeted to modify particular subpopulations of monocytes.


Castrillo A, Tontonoz P. Nuclear Receptors in Macrophage Biology: At the Crossroads of Lipid Metabolism and Inflammation.
Annual Review of Cell and Developmental Biology. 2004;20(1):455–80.

ABSTRACT: Macrophages are essential modulators of lipid metabolism and the innate immune system. Lipid and inflammatory pathways induced in activated macrophages are central to the pathogenesis of human diseases including atherosclerosis. Recent work has shown that expression of genes involved in lipid uptake and cholesterol efflux in macrophages is controlled by peroxisome proliferator-activated receptors (PPARs) and liver X receptors (LXRs). Other studies have implicated these same receptors in the modulation of macrophage inflammatory gene expression. Together, these observations position PPARs and LXRs at the crossroads of lipid metabolism and inflammation and suggest that these receptors may serve to integrate these pathways in the control of macrophage gene expression. In this review, we summarize recent work that has advanced our understanding of the roles of PPARs and LXRs in macrophage biology and discuss the implication of these results for cardiovascular physiology and disease.


Rosenberger CM, Finlay BB. Phagocyte sabotage: disruption of macrophage signalling by bacterial pathogens.
Nature Reviews Molecular Cell Biology. 2003 May 1;4(5):385–96.

ABSTRACT: Macrophages function at the front line of immune defences against incoming pathogens. But the ability of macrophages to internalize bacteria, migrate, recruit other immune cells to the site of infection and influence the nature of the immune response can provide unintended benefits for bacterial pathogens that are able to subvert or co-opt these normally effective defences. This review highlights recent advances in our understanding of the many interference strategies that are used by bacterial pathogens to undermine macrophage signalling.


Mosser DM. The Many Faces of Macrophage Activation.
J Leukoc Biol. 2003 Feb 1;73(2):209–12.

ABSTRACT: It used to be easy. In the old days (∼8 years ago), activated macrophages were simply defined as cells that secreted inflammatory mediators and killed intracellular pathogens. Things are becoming progressively more complicated in the world of leukocyte biology. Activated macrophages may be a more heterogenous group of cells than originally appreciated, with different physiologies and performing distinct immunological functions. The first hint of this heterogeneity came with the characterization of the “alternatively activated macrophage” [1]. The exposure of macrophages to interleukin (IL)-4 or glucocorticoids induced a population of cells that up-regulated certain phagocytic receptors but failed to produce nitrogen radicals [2] and as a result, were relatively poor at killing intracellular pathogens. Recent studies have shown that these alternatively activated cells produce several components involved in the synthesis of the extracellular matrix (ECM) [3], suggesting their primary role may be involved in tissue repair rather than microbial killing. It turns out that the name alternatively activated macrophage may be unfortunate for a few reasons. First, although these cells express some markers of activation, they have not been exposed to the classical, activating stimuli, interferon-γ (IFN-γ) and lipopolysaccharide (LPS). Second, and more importantly, the name implies that this is the only other way to activate a macrophage. Recent studies suggest that this may not be the case. Exposure of macrophages to classical activating signals in the presence of immunoglobulin G (IgG) immune complexes induced the production of a cell type that was fundamentally different from the classically activated macrophage. These cells generated large amounts of IL-10 and as a result, were potent inhibitors of acute inflammatory responses to bacterial endotoxin [4]. These activated macrophages have been called type 2-activated macrophages [5] because of their ability to induce T helper cell type 2 (Th2) responses that were predominated by IL-4 [6], leading to IgG class-switching by B cells. Thus, at this time, there appears to be at least three different populations of activated macrophages with three distinct biological functions. The first and most well described is the classically activated macrophage whose role is as an effector cell in Th1 cellular immune responses. The second type of cell, the alternatively activated macrophage, appears to be involved in immunosuppression and tissue repair. The most recent addition to this list is the type 2-activated macrophage, which is anti-inflammatory and preferentially induces Th2-type humoral-immune responses to antigen. Together, these three populations of cells may form their own regulatory network to prevent a well-intentioned immune response from progressing to immunopathology.


Calandra T, Roger T. Macrophage migration inhibitory factor: a regulator of innate immunity.
Nature Reviews Immunology. 2003 Oct 1;3(10):791–800.

ABSTRACT: For more than a quarter of a century, macrophage migration inhibitory factor (MIF) has been a mysterious cytokine. In recent years, MIF has assumed an important role as a pivotal regulator of innate immunity. MIF is an integral component of the host antimicrobial alarm system and stress response that promotes the pro-inflammatory functions of immune cells. A rapidly increasing amount of literature indicates that MIF is implicated in the pathogenesis of sepsis, and inflammatory and autoimmune diseases, suggesting that MIF-directed therapies might offer new treatment opportunities for human diseases in the future.


Dong Z, Fidler IJ. Macrophages.
Encyclopedia of Cancer (Second Edition) [Internet]. New York: Academic Press; 2002 [cited 2012 Jun 29]. p. 77–88.

CONTENTS: I. Introduction II. Role of Macrophages in Homeostasis III. Role of Macrophages in Tumor Angiogenesis and Progression IV. Tumoricidal Activation of Macrophages V. Macrophage–Tumor Cell Interaction VI. Mechanisms for Macrophage Recognition of Tumor Cells VII. Suppression of Tumor Angiogenesis by Macrophage-Derived Factors VIII. Macrophage Infiltration into Tumors IX. Systemic Activation of Macrophages by Liposomes Containing Immunomodulators X. Therapy of Cancer Metastasis in Murine Models XI. Therapy of Autochthonous Lung Metastasis in Dogs with Osteogenic Sarcoma XII. Clinical StudiesXI. Conclusions See Also the Following Articles Glossary Bibliography


Paulnock DM, editor. Macrophages : A practical approach.
Oxford: Oxford University Press; 2000.

SUMMARY: Macrophages are an important part of the immune response and are characterized by their ability to phagocytose foreign matter. However the difficulties involved in macrophage isolation mean they are some of the body’s least explored cells. Macrophage Methodology describes how to isolate moderate to high yields of viable cells from a variety of specific tissue sites under both normal and pathological conditions and then goes on to give protocols for macrophage purification. The third chapter covers techniques used to identify and measure endocytic and phagocytic capabilities using immunochemistry and fluorescent analysis. Chapter four identifies the key issues relating to the study of macrophages as antigen presenting cells and has protocols for the major assays used to measure antigen processing and presentation. Also covered are the theoretical and practical issues related to the processing and presentation of intracellular pathogens for which macrophages are the major host cell. The methods described for measuring macrophage secretory products concentrate on bioassays for molecules where no ELISA is available. The next two chapters cover measuring macrophage activity in vitro and in vivo. Finally methods are described for the analysis of gene expression in macrophages. A variety of broad techniques have been brought together in one affordable volume to make Macrophage Methodology an essential buy for anyone studying macrophages.


Kornfeld H, Mancino G, Colizzi V.
The role of macrophage cell death in tuberculosis.
Cell Death and Differentiation. 1999 Jan 11;6(1):71–8.

ABSTRACT: Studies of host responses to infection have traditionally focused on the direct antimicrobial activity of effector molecules (antibodies, complement, defensins, reactive oxygen and nitrogen intermediates) and immunocytes (macrophages, lymphocytes, and neutrophils among others). The discovery of the systems for programmed cell death of eukaryotic cells has revealed a unique role for this process in the complex interplay between microorganisms and their cellular targets or responding immunocytes. In particular, cells of the monocyte/macrophage lineage have been demonstrated to undergo apoptosis following intracellular infection with certain pathogens that are otherwise capable of surviving within the hostile environment of the phagosome or which can escape the phagosome. Mycobacterium tuberculosis is a prototypical ‘intracellular parasite’ of macrophages, and the direct induction of macrophage apoptosis by this organism has recently been reported from several laboratories. This paper reviews the current understanding of the mechanism and regulation of macrophage apoptosis in response to M. tuberculosis and examines the role this process plays in protective immunity and microbial virulence.


van den Berg WB, van Lent PLEM. CHAPTER 16 – The Role of Macrophages in Chronic Arthritis.
Immunobiology. 1996 Oct;195(4–5):614–23.

ABSTRACT: Rheumatoid arthritis is characterized by a mononuclear infiltrate in the synovial tissue of the affected joints, considerable thickening of the synovial lining layer and concomitant destruction of cartilage and bone. Macrophages probably play a central role and the contribution of the synovial lining macrophages is addressed in studies in experimental murine arthritis models. Emphasis is given to the involvement in arthritis expression and cartilage destruction. The role of TNF-α and IL-1, and the modulatory cytokines IL-4/ IL-10 is briefly discussed.


Gordon S, Perry V, Rabinowitz S, Chung L, Rosen H. Plasma membrane receptors of the mononuclear phagocyte system.
Journal of cell science. Supplement. 1988;9:1.

ABSTRACT: Plasma membrane receptors control macrophage activities such as growth, differentiation and activation, migration, recognition, endocytosis and secretion. They are therefore important in a wide range of physiological and pathological processes including host defence, inflammation and repair, involving all systems of the body including the arterial wall and nervous system. The versatile responsiveness of these cells to various stimuli depends on their ability to express a large repertoire of receptors, some restricted to macrophages and closely related cells, others common to many cell types. This volume contains reviews of the macrophage receptors that are best characterized and deals with aspects of signal transduction and function of the actin cytoskeleton. Our introduction is designed to place these topics in perspective. We summarize features of constitutive and induced mononuclear phagocyte distribution within the body and consider receptor expression and macrophage responses in the context of cell heterogeneity associated with its complex life history. We classify receptors discussed in detail in other chapters, list ligand-binding properties that are not as well defined, and briefly review general features of receptor function in macrophages. An understanding of macrophage receptor biology should bring insights into the contribution of these cells to physiology and disease and result in an improved ability to manipulate activities within the mononuclear phagocyte system.


Gordon S, Perry V, Rabinowitz S, Chung L, Rosen H. Plasma membrane receptors of the mononuclear phagocyte system.
Journal of cell science. Supplement. 1988;9:1.

ABSTRACT: Plasma membrane receptors control macrophage activities such as growth, differentiation and activation, migration, recognition, endocytosis and secretion. They are therefore important in a wide range of physiological and pathological processes including host defence, inflammation and repair, involving all systems of the body including the arterial wall and nervous system. The versatile responsiveness of these cells to various stimuli depends on their ability to express a large repertoire of receptors, some restricted to macrophages and closely related cells, others common to many cell types. This volume contains reviews of the macrophage receptors that are best characterized and deals with aspects of signal transduction and function of the actin cytoskeleton. Our introduction is designed to place these topics in perspective. We summarize features of constitutive and induced mononuclear phagocyte distribution within the body and consider receptor expression and macrophage responses in the context of cell heterogeneity associated with its complex life history. We classify receptors discussed in detail in other chapters, list ligand-binding properties that are not as well defined, and briefly review general features of receptor function in macrophages. An understanding of macrophage receptor biology should bring insights into the contribution of these cells to physiology and disease and result in an improved ability to manipulate activities within the mononuclear phagocyte system.


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