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

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.
[toggle_content title=”Summary”]

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.



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.
[toggle_content title=”Summary”]

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.



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.
[toggle_content title=”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.



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



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.
[toggle_content title=”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.
[toggle_content title=”Introduction”]

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.



Dong Z, Fidler IJ.
Encyclopedia of Cancer (Second Edition) [Internet]. New York: Academic Press; 2002 [cited 2012 Jun 29]. p. 77–88.
[toggle_content title=”Table of 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 Studies
XI. Conclusions
See Also the Following Articles



Paulnock DM, editor.
Macrophages : A practical approach.
Oxford: Oxford University Press; 2000.
[toggle_content title=”Description”]

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.
[toggle_content title=”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.