HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mosser, D. M. Search for Related Content PubMed PubMed Citation Articles by Mosser, D. M. Related Collections Related Articles

(Journal of Leukocyte Biology. 2003;73:209-212.)
© 2003 by Society for Leukocyte Biology

The many faces of macrophage activation

Cell Biology and Molecular Genetics, University of Maryland, College Park

Correspondence: David M. Mosser, Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742. E-mail: dm268{at}umail.umd.edu

Key Words: immunoregulation • autoimmunity • IFN- • IL-4 • alternatively activated macrophage • type 2-activated macrophage

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- (IFN-) 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.

THE CLASSICALLY ACTIVATED MACROPHAGE

As Yogi Berra might say, let’s start from the beginning. It is important to remember that macrophages become classically activated by exposure to two signals. The first is the obligatory cytokine IFN-, which primes macrophages for activation but does not in itself activate macrophages [⁷ ]. The second signal is tumor necrosis factor (TNF) itself or an inducer of TNF. Exogenous TNF can act as the second signal, but the physiologically relevant second signal is generally the result of Toll-like receptor (TLR) ligation, which induces endogenous TNF production by the macrophage itself. Thus, classically activated macrophages are developed in response to IFN-, along with exposure to a microbe or microbial product such as LPS. In the murine system, these cells are now easily identified by virtue of their production of nitric oxide (NO) [⁸ , ⁹ ]. Macrophages that have been primed with IFN- alone should not make NO, provided the system is free of LPS (a common contaminant in recombinant IFN-). In the human system, the activation of macrophages is somewhat more difficult to definitively determine, as monocyte-derived macrophages from peripheral blood generally do not produce NO in response to the classical activating stimuli. These cells must be identified by a variety of biochemical and functional criteria (Table 1 ), including the up-regulation of surface molecules such as MHC class II and B-7 (CD86) and an enhanced ability to present antigen and kill intracellular pathogens. With the application of microarrays, the analysis of classically activated macrophages has entered into a new era of complexity. Remarkably, 25% of the observed genes exhibited alterations in their expression upon macrophage activation [¹⁰ ]. The problem now becomes selecting which of the several hundred genes that are induced or suppressed during activation are true and reliable markers of macrophage activation.

Tissue macrophages can be seen in organized collections of cells called granulomas, where they are frequently surrounded by T cells producing activating cytokines. These granuloma macrophages are a rich source of inflammatory cytokines, toxic radicals, and inflammatory lipid mediators. These products are capable of causing extensive tissue damage to the host. For example, the observation that tumors frequently developed proximal to old tuberculosis scars [¹⁵ ] illustrates the destructive and mutagenic potential of the activated macrophages that are frequently found there. The immunopathology associated with many type 1 autoimmune diseases has the activated macrophage as the main protagonist [¹⁶ ]. Thus, the activity of these cells must be carefully regulated to prevent uncontrolled tissue destruction. Signals to down-regulate macrophage activation may come from within the macrophage itself or from surrounding cells. The immunoregulatory cytokines transforming growth factor (TGF)-ß and IL-10 play an important role in dampening macrophage activation. Knockout mice lacking either of these two cytokines have proven to be hypersusceptible to inflammatory pathologies [¹⁷ , ¹⁸ ]. A recently described family of macrophage receptor tyrosine kinases in the stem cell-derived tyrosine kinase receptor (STK/RON) family has been implicated in the inhibition of macrophage activation [¹⁹ ]. The ligation of RON with macrophage stimulatory protein appears to induce arginase activity (see below) and inhibit NO production. Thus, the ligation of this family of receptors may alter the phenotype of these cells into ones that resemble the alternatively activated macrophages described below. Finally, cell death by apoptosis cannot be ignored as an important immunoregulatory mechanism. The direct removal of inflammatory cells as well as the induction of anti-inflammatory TGF-ß following apoptotic cell removal [²⁰ ] contribute to this effect.

One of the most interesting, new areas of inquiry in this field is determining how intracellular pathogens interfere with signaling to prevent macrophage activation. The protozoan parasite Leishmania spp [²¹ ] and Mycobacterium spp [²² ] have provided the best examples of such interference. Infection of macrophages with either of these organisms prevents the macrophage from becoming fully activated in response to IFN-. The molecules and mechanisms by which these organisms circumvent cellular immunity will likely reveal important information about the process of macrophage activation itself.

THE ALTERNATIVELY ACTIVATED MACROPHAGE

In the early 1990s, while examining the regulation of mannose receptor expression on elicited macrophages, Gordon and colleagues [¹ ] noticed that a particularly efficient way to induce receptor expression was to treat these macrophages with IL-4. The authors concluded that macrophages treated with IL-4 assumed an "alternative activation phenotype." This represents the first description of a macrophage that exhibited signs of activation but was clearly distinct from its classically activated counterpart. Subsequent studies by Goerdt and Orfanos [²³ ] have championed this cell as a regulatory macrophage with diverse biological roles different from the classically activated cell. These cells fail to make NO by virtue of their induction of arginase [²⁴ ] and consequently, are compromised in their ability to kill intracellular microbes. Although they up-regulate some MHC class II molecules, they are not efficient at antigen presentation, and in many instances, they actually inhibit T cell proliferation. The suppressive activity of these macrophages extends to mitogen-activated T cells, which show a significantly diminished proliferative and secretory response in the presence of alternatively activated macrophages [²⁵ ]. The signature cytokines produced by these alternatively activated macrophages are IL-10 and IL-1 receptor antagonist. In the lung, it is thought that alternatively activated macrophages may provide negative regulatory signals to protect the host from overzealous inflammatory responses to environmental stimuli [²⁶ ]. Recent studies on this cell population have begun to focus on their potential to mediate wound-healing, angiogenesis, and ECM deposition. Alternatively activated macrophages produce high levels of fibronectin and a matrix-associated protein, ßIG-H3 [³ ], and they promote fibrogenesis from fibroblastoid cells [²⁷ ]. The induction of arginase in these cells may lead to polyamine and proline biosynthesis, promoting cell growth, collagen formation, and tissue repair [²⁸ ].

The in vivo schistosome infection model has proven to be an invaluable one to unravel the function of altered macrophage metabolism caused by type 2 cytokines [²⁸ ]. Unlike many of the autoimmune models mentioned above, in the Schistosome model, type 2 immune responses correlate with pathology, whereas type 1 responses can ameliorate tissue destruction. This model has revealed that a competition for arginine metabolism within macrophages may be a key determinant of macrophage physiology. When macrophages are treated with type 1 cytokines, the iNOS2 enzyme produces NO from arginine. When macrophages are exposed to type 2 cytokines, Arg-1 is induced and metabolizes arginine to urea and ornithine, a precursor of polyamines and proline. Polyamines are involved in cell growth and division, whereas proline is a key component of collagen. In this elegant model system, Wynn and colleagues [²⁸ ] demonstrated unequivocally that Arg-1 levels correlate directly with Schistosome egg-induced pathology, whereas iNOS levels inversely correlate with pathology. Recently, macrophages from the (Th2-prone) BALB/c mice were shown to make more arginase than macrophages from the Th1-prone C57Bl/6 mice [²⁹ ]. Thus, the alternatively activated macrophage may serve more of a regulatory and recovery function than the effector killing functions that are associated with classically activated macrophages.

Although the alternatively activated macrophage has been investigated for only slightly more than 5 years, there exists a solid battery of markers available to identify this cell type (Table 1) . In addition to arginase induction, these cells make a signature chemokine, originally named AMAC-1 [³⁰ ]. They react well with monoclonal antibodies to a specific form of CD163 and an uncharacterized MS-1 antigen. Finally, two transcription factors, FIZZ1 and Ym1, appear to be preferentially induced in IL-4-treated macrophages [³¹ ].

THE TYPE II-ACTIVATED MACROPHAGE

The type II-activated macrophage was initially identified during an examination of conditions under which IL-12 transcription was terminated. It was observed that the ligation of FcRs on activated macrophages unexpectedly turned off IL-12 synthesis [³² ] and induced the secretion of large amounts of IL-10 [³³ ]. A variety of immune complexes and a number of different activating stimuli were used, and in all cases, FcR ligation resulted in a specific and reciprocal alteration in the production of these two cytokines [⁴ ]. Similar to the classically activated macrophages described above, the type II activation phenotype required two signals. The first signal was the ligation of FcRs. However, receptor ligation had to be coupled with a macrophage stimulatory signal to influence cytokine production. Stimuli included those that signal through any of the TLRs, as well as through CD40 or CD44. The type II phenotypic switch following FcR ligation worked on unprimed and IFN--primed macrophages. Type II-activated macrophages are clearly distinct from alternatively activated macrophages described above, as they do not induce arginase, and with the exception of IL-12 and IL-10, the production of many of the other cytokines produced by classically activated macrophages, such as TNF, IL-1, and IL-6, remains intact [⁴ ].

The dramatic induction of IL-10 by these macrophages suggested that they would have anti-inflammatory properties. To test this, an acute model of LPS lethality was implemented. Type II-activated macrophages were generated in vitro and transferred into mice, which then received six times the lethal dose (90) of LPS. Mice that received 1 x 10⁶ type II macrophages remained completely viable and healthy throughout the observation period, whereas mice that received control macrophages succumbed to lethal endotoxemia within 48 h [⁴ ]. To show that this effect was a result of IL-10 secretion, type II-activated macrophages from IL-10-/- mice were used in parallel. These macrophages failed to rescue mice from lethal endotoxemia. Thus, by virtue of their secretion of IL-10, the type II-activated macrophage exerts a potent anti-inflammatory effect that can be exploited to prevent acute pathologies, such as those associated with LPS endotoxemia.

The name, type II-activated macrophages, was derived from their ability to preferentially induce Th2 adaptive immune responses. In the initial in vitro studies, classically or type II-activated macrophages were used as antigen presenting cells (APC). Classically activated macrophages stimulated T cells to produce primarily IFN- in response to antigen, whereas type II-activated macrophages induced T cells to produce high levels of IL-4 [⁶ ]. This bias in T cell cytokine production by these two populations of APC was stable and preserved when T cells were subsequently restimulated under a variety of nonbiasing conditions. T cell cytokine production correlated with APC cytokine production. IL-12 secretion by classically activated macrophages induced IFN- production by T cells, whereas IL-10 secretion by type II-activated macrophages resulted in IL-4 production by T cells [⁶ ].

To determine the extent to which type II-activated macrophages could influence antibody responses to antigen, mice were injected with type II- or classically activated macrophages along with ovalbumin (OVA) antigen in the absence of any other adjuvant. Mice vaccinated with OVA in the presence of classically activated macrophages made only modest IgG-antibody responses to antigen [⁵ ]. Mice vaccinated with OVA in the presence of type II-activated macrophages, however, made significantly more IgG, and the majority of the IgG was of the IgG1 isotype. This observation suggested that the presence of type II-activated macrophages alone was sufficient to induce (Th2-like) IgG class-switching. Thus, the ligation of FcR on activated macrophages by antigen-IgG complexes induced T cells to produce IL-4, which in turn induced B cells to produce IgG1 in response to that antigen.

These studies demonstrate that antigen binding to the FcR on activated macrophages will preferentially induce a Th2-like response. Thus, they predict that IgG itself can be a strong inducer of humoral immunity and an inhibitor of cell-mediated immunity by virtue of its ability to change the phenotype of the APC. These observations may have important, practical implications, as they suggest that reagents that ligate the FcR on activated macrophages may have anti-inflammatory properties that can be exploited to ameliorate autoimmune diseases. These studies may also have particular relevance to autoimmunity, where activated macrophages likely represent important APC’s.

SUMMARY

Macrophage heterogeneity used to be a research topic on which the careers of many postdoctoral fellows were misspent. The lack of definitive markers and dubious biochemical assays prevented the unequivocal identification of specific cell subsets. There has now been significant progress in establishing the heterogeneity of activated macrophages. There are at least three distinct populations of macrophages, and each cell type appears to have different biological roles. The interplay among these populations of cells may help to shape not only the magnitude but also the character of the immune response. The manipulation of these cells may lead to new approaches to treat or prevent disease.

Received June 25, 2002; accepted October 1, 2002.

REFERENCES

1. Stein, M., Keshav, S., Harris, N., Gordon, S. (1992) Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation J. Exp. Med. 176,287-292[Abstract/Free Full Text]
2. Modolell, M., Corraliza, I. M., Link, F., Soler, G., Eichmann, K. (1995) Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by TH1 and TH2 cytokines Eur. J. Immunol. 25,1101-1104[Medline]
3. Gratchev, A., Guillot, P., Hakiy, N., Politz, O., Orfanos, C. E., Schledzewski, K., Goerdt, S. (2001) Alternatively activated macrophages differentially express fibronectin and its splice variants and the extracellular matrix protein betaIG-H3 Scand. J. Immunol. 53,386-392[CrossRef][Medline]
4. Gerber, J. S., Mosser, D. M. (2001) Reversing lipopolysaccharide toxicity by ligating the macrophage Fc gamma receptors J. Immunol. 166,6861-6868[Abstract/Free Full Text]
5. Anderson, C. A., Mosser, D. M. (2002) A novel phenotype for activated macrophages: the type II activated macrophage J. Leukoc. Biol 72,101-106[Abstract/Free Full Text]
6. Anderson, C. F., Mosser, D. M. (2002) Cutting edge: biasing immune responses by directing antigen to macrophage Fc gamma receptors J. Immunol. 168,3697-3701[Abstract/Free Full Text]
7. Nathan, C. (1991) Mechanisms and modulation of macrophage activation Behring Inst. Mitt. Feb.,200-207
8. Hibbs, J. B., Jr (2002) Infection and nitric oxide J. Infect. Dis. 185(Suppl. 1),S9-S17
9. MacMicking, J., Xie, Q. W., Nathan, C. (1997) Nitric oxide and macrophage function Annu. Rev. Immunol. 15,323-350[CrossRef][Medline]
10. Ehrt, S., Schnappinger, D., Bekiranov, S., Drenkow, J., Shi, S., Gingeras, T. R., Gaasterland, T., Schoolnik, G., Nathan, C. (2001) Reprogramming of the macrophage transcriptome in response to interferon-gamma and Mycobacterium tuberculosis: signaling roles of nitric oxide synthase-2 and phagocyte oxidase J. Exp. Med. 194,1123-1140[Abstract/Free Full Text]
11. Mosser, D. M., Handman, E. (1992) Treatment of murine macrophages with interferon-gamma inhibits their ability to bind leishmania promastigotes J. Leukoc. Biol. 52,369-376[Abstract]
12. Ezekowitz, R. A., Gordon, S. (1984) Alterations of surface properties by macrophage activation: expression of receptors for Fc and mannose-terminal glycoproteins and differentiation antigens Contemp. Top. Immunobiol. 13,33-56[Medline]
13. Gruenheid, S., Gros, P. (2000) Genetic susceptibility to intracellular infections: Nramp1, macrophage function and divalent cations transport Curr. Opin. Microbiol. 3,43-48[CrossRef][Medline]
14. Carlin, J. M., Borden, E. C., Sondel, P. M., Byrne, G. I. (1989) Interferon-induced indoleamine 2,3-dioxygenase activity in human mononuclear phagocytes J. Leukoc. Biol. 45,29-34[Abstract]
15. Dacosta, N. A., Kinare, S. G. (1991) Association of lung carcinoma and tuberculosis J. Postgrad. Med. 37,185-189[Medline]
16. Flavell, R. A. (2002) The relationship of inflammation and initiation of autoimmune disease: role of TNF super family members Curr. Top. Microbiol. Immunol. 266,1-9[Medline]
17. Ho, A. S., Moore, K. W. (1994) Interleukin-10 and its receptor Ther. Immunol. 1,173-185[Medline]
18. Reed, S. G. (1999) TGF-beta in infections and infectious diseases Microbes Infect 1,1313-1325[CrossRef][Medline]
19. Morrison, A. C., Correll, P. H. (2002) Activation of the stem cell-derived tyrosine kinase/RON receptor tyrosine kinase by macrophage-stimulating protein results in the induction of arginase activity in murine peritoneal macrophages J. Immunol. 168,853-860[Abstract/Free Full Text]
20. Huynh, M. L., Fadok, V. A., Henson, P. M. (2002) Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation J. Clin. Invest. 109,41-50[CrossRef][Medline]
21. Nandan, D., Knutson, K. L., Lo, R., Reiner, N. E. (2000) Exploitation of host cell signaling machinery: activation of macrophage phosphotyrosine phosphatases as a novel mechanism of molecular microbial pathogenesis J. Leukoc. Biol. 67,464-470[Abstract]
22. Ting, L. M., Kim, A. C., Cattamanchi, A., Ernst, J. D. (1999) Mycobacterium tuberculosis inhibits IFN-gamma transcriptional responses without inhibiting activation of STAT1 J. Immunol. 163,3898-3906[Abstract/Free Full Text]
23. Goerdt, S., Orfanos, C. E. (1999) Other functions, other genes: alternative activation of antigen-presenting cells Immunity 10,137-142[CrossRef][Medline]
24. Rutschman, R., Lang, R., Hesse, M., Ihle, J. N., Wynn, T. A., Murray, P. J. (2001) Cutting edge: Stat6-dependent substrate depletion regulates nitric oxide production J. Immunol. 166,2173-2177[Abstract/Free Full Text]
25. Schebesch, C., Kodelja, V., Muller, C., Hakij, N., Bisson, S., Orfanos, C. E., Goerdt, S. (1997) Alternatively activated macrophages actively inhibit proliferation of peripheral blood lymphocytes and CD4+ T cells in vitro Immunology 92,478-486[CrossRef][Medline]
26. Goerdt, S., Politz, O., Schledzewski, K., Birk, R., Gratchev, A., Guillot, P., Hakiy, N., Klemke, C. D., Dippel, E., Kodelja, V., Orfanos, C. E. (1999) Alternative versus classical activation of macrophages Pathobiology 67,222-226[CrossRef][Medline]
27. Song, E., Ouyang, N., Horbelt, M., Antus, B., Wang, M., Exton, M. S. (2000) Influence of alternatively and classically activated macrophages on fibrogenic activities of human fibroblasts Cell. Immunol. 204,19-28[CrossRef][Medline]
28. Hesse, M., Modolell, M., La Flamme, A. C., Schito, M., Fuentes, J. M., Cheever, A. W., Pearce, E. J., Wynn, T. A. (2001) Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism J. Immunol. 167,6533-6544[Abstract/Free Full Text]
29. Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J., Hill, A. M. (2000) M-1/M-2 macrophages and the Th1/Th2 paradigm J. Immunol. 164,6166-6173[Abstract/Free Full Text]
30. Kodelja, V., Muller, C., Politz, O., Hakij, N., Orfanos, C. E., Goerdt, S. (1998) Alternative macrophage activation-associated CC-chemokine-1, a novel structural homologue of macrophage inflammatory protein-1 alpha with a Th2-associated expression pattern J. Immunol. 160,1411-1418[Abstract/Free Full Text]
31. Raes, G., De Baetselier, P., Noel, W., Beschin, A., Brombacher, F., Hassanzadeh, G. G. (2002) Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages J. Leukoc. Biol. 71,597-602[Abstract/Free Full Text]
32. Sutterwala, F. S., Noel, G. J., Clynes, R., Mosser, D. M. (1997) Selective suppression of interleukin-12 induction after macrophage receptor ligation J. Exp. Med. 185,1977-1985[Abstract/Free Full Text]
33. Sutterwala, F. S., Noel, G. J., Salgame, P., Mosser, D. M. (1998) Reversal of proinflammatory responses by ligating the macrophage Fcgamma receptor type I J. Exp. Med. 188,217-222[Abstract/Free Full Text]

This article has been cited by other articles:

				C. Shi, M. Sakuma, T. Mooroka, A. Liscoe, H. Gao, K. J. Croce, A. Sharma, D. Kaplan, D. R. Greaves, Y. Wang, et al. Down-regulation of the forkhead transcription factor Foxp1 is required for monocyte differentiation and macrophage function Blood, December 1, 2008; 112(12): 4699 - 4711. [Abstract] [Full Text] [PDF]

				B. Calderon, A. Suri, X. O. Pan, J. C. Mills, and E. R. Unanue IFN-{gamma}-Dependent Regulatory Circuits in Immune Inflammation Highlighted in Diabetes J. Immunol., November 15, 2008; 181(10): 6964 - 6974. [Abstract] [Full Text] [PDF]

				J. Bystrom, I. Evans, J. Newson, M. Stables, I. Toor, N. van Rooijen, M. Crawford, P. Colville-Nash, S. Farrow, and D. W. Gilroy Resolution-phase macrophages possess a unique inflammatory phenotype that is controlled by cAMP Blood, November 15, 2008; 112(10): 4117 - 4127. [Abstract] [Full Text] [PDF]

				I. Stamm, M. Mohr, P. S. Bridger, E. Schropfer, M. Konig, W. C. Stoffregen, E. A. Dean-Nystrom, G. Baljer, and C. Menge Epithelial and Mesenchymal Cells in the Bovine Colonic Mucosa Differ in Their Responsiveness to Escherichia coli Shiga Toxin 1 Infect. Immun., November 1, 2008; 76(11): 5381 - 5391. [Abstract] [Full Text] [PDF]

				M. Poupot, J.-J. Fournie, and R. Poupot Trogocytosis and killing of IL-4-polarized monocytes by autologous NK cells J. Leukoc. Biol., November 1, 2008; 84(5): 1298 - 1305. [Abstract] [Full Text] [PDF]

				M. Benoit, B. Desnues, and J.-L. Mege Macrophage Polarization in Bacterial Infections J. Immunol., September 15, 2008; 181(6): 3733 - 3739. [Abstract] [Full Text] [PDF]

				G. Varga, J. Ehrchen, A. Tsianakas, K. Tenbrock, A. Rattenholl, S. Seeliger, M. Mack, J. Roth, and C. Sunderkoetter Glucocorticoids induce an activated, anti-inflammatory monocyte subset in mice that resembles myeloid-derived suppressor cells J. Leukoc. Biol., September 1, 2008; 84(3): 644 - 650. [Abstract] [Full Text] [PDF]

				M. Alsharifi, M. Lobigs, J. Bettadapura, A. Koskinen, and A. Mullbacher Restricted Semliki Forest virus replication in perforin and Fas-ligand double-deficient mice J. Gen. Virol., August 1, 2008; 89(8): 1942 - 1944. [Abstract] [Full Text] [PDF]

				J. J. Reece, M. C. Siracusa, T. L. Southard, C. F. Brayton, J. F. Urban Jr., and A. L. Scott Hookworm-Induced Persistent Changes to the Immunological Environment of the Lung Infect. Immun., August 1, 2008; 76(8): 3511 - 3524. [Abstract] [Full Text] [PDF]

				T. L. Bonfield, M. J. Thomassen, C. F. Farver, S. Abraham, M. T. Koloze, X. Zhang, D. M. Mosser, and D. A. Culver Peroxisome Proliferator-Activated Receptor-{gamma} Regulates the Expression of Alveolar Macrophage Macrophage Colony-Stimulating Factor J. Immunol., July 1, 2008; 181(1): 235 - 242. [Abstract] [Full Text] [PDF]

				G. Chan, E. R. Bivins-Smith, M. S. Smith, P. M. Smith, and A. D. Yurochko Transcriptome Analysis Reveals Human Cytomegalovirus Reprograms Monocyte Differentiation toward an M1 Macrophage J. Immunol., July 1, 2008; 181(1): 698 - 711. [Abstract] [Full Text] [PDF]

				A. M. Timmer and V. Nizet IKK{beta}/NF-{kappa}B and the miscreant macrophage J. Exp. Med., June 9, 2008; 205(6): 1255 - 1259. [Abstract] [Full Text] [PDF]

				Y.-C. Chang, T.-C. Chen, C.-T. Lee, C.-Y. Yang, H.-W. Wang, C.-C. Wang, and S.-L. Hsieh Epigenetic control of MHC class II expression in tumor-associated macrophages by decoy receptor 3 Blood, May 15, 2008; 111(10): 5054 - 5063. [Abstract] [Full Text] [PDF]

				J. E. Hughes, S. Srinivasan, K. R. Lynch, R. L. Proia, P. Ferdek, and C. C. Hedrick Sphingosine-1-Phosphate Induces an Antiinflammatory Phenotype in Macrophages Circ. Res., April 25, 2008; 102(8): 950 - 958. [Abstract] [Full Text] [PDF]

				J. W. Chen, M. O. Breckwoldt, E. Aikawa, G. Chiang, and R. Weissleder Myeloperoxidase-targeted imaging of active inflammatory lesions in murine experimental autoimmune encephalomyelitis Brain, April 1, 2008; 131(4): 1123 - 1133. [Abstract] [Full Text] [PDF]

				Y. Tsuda, K. Shigematsu, M. Kobayashi, D. N. Herndon, and F. Suzuki Role of Polymorphonuclear Neutrophils on Infectious Complications Stemming from Enterococcus faecalis Oral Infection in Thermally Injured Mice J. Immunol., March 15, 2008; 180(6): 4133 - 4138. [Abstract] [Full Text] [PDF]

				C. T. Migliaccio, M. C. Buford, F. Jessop, and A. Holian The IL-4R{alpha} pathway in macrophages and its potential role in silica-induced pulmonary fibrosis J. Leukoc. Biol., March 1, 2008; 83(3): 630 - 639. [Abstract] [Full Text] [PDF]

				J.-E. Ghia, F. Galeazzi, D. C. Ford, C. M. Hogaboam, B. A. Vallance, and S. Collins Role of M-CSF-dependent macrophages in colitis is driven by the nature of the inflammatory stimulus Am J Physiol Gastrointest Liver Physiol, March 1, 2008; 294(3): G770 - G777. [Abstract] [Full Text] [PDF]

				V. Bourlier, A. Zakaroff-Girard, A. Miranville, S. De Barros, M. Maumus, C. Sengenes, J. Galitzky, M. Lafontan, F. Karpe, K.N. Frayn, et al. Remodeling Phenotype of Human Subcutaneous Adipose Tissue Macrophages Circulation, February 12, 2008; 117(6): 806 - 815. [Abstract] [Full Text] [PDF]

				C.-S. Chiang, F.-H. Chen, J.-H. Hong, P.-S. Jiang, H.-L. Huang, C.-C. Wang, and W. H. McBride Functional phenotype of macrophages depends on assay procedures Int. Immunol., February 1, 2008; 20(2): 215 - 222. [Abstract] [Full Text] [PDF]

				L. Schiffer, R. Bethunaickan, M. Ramanujam, W. Huang, M. Schiffer, H. Tao, M. M. Madaio, E. P. Bottinger, and A. Davidson Activated Renal Macrophages Are Markers of Disease Onset and Disease Remission in Lupus Nephritis J. Immunol., February 1, 2008; 180(3): 1938 - 1947. [Abstract] [Full Text] [PDF]

				H. Li, Y. Zhang, Z. H. Ning, X. M. Deng, Z. X. Lian, and N. Li Effect of Selection for Phagocytosis in Dwarf Chickens on Immune and Reproductive Characters Poult. Sci., January 1, 2008; 87(1): 41 - 49. [Abstract] [Full Text] [PDF]

				U. Gaur, S. C. Roberts, R. P. Dalvi, I. Corraliza, B. Ullman, and M. E. Wilson An Effect of Parasite-Encoded Arginase on the Outcome of Murine Cutaneous Leishmaniasis J. Immunol., December 15, 2007; 179(12): 8446 - 8453. [Abstract] [Full Text] [PDF]

				M. M. Tiemessen, A. L. Jagger, H. G. Evans, M. J. C. van Herwijnen, S. John, and L. S. Taams CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages PNAS, December 4, 2007; 104(49): 19446 - 19451. [Abstract] [Full Text] [PDF]

				J. Du, T. Tran, C. Fu, and D. W. Sretavan Upregulation of EphB2 and ephrin-B2 at the Optic Nerve Head of DBA/2J Glaucomatous Mice Coincides with Axon Loss Invest. Ophthalmol. Vis. Sci., December 1, 2007; 48(12): 5567 - 5581. [Abstract] [Full Text] [PDF]

				M. Moeller, M. H. Kershaw, R. Cameron, J. A. Westwood, J. A. Trapani, M. J. Smyth, and P. K. Darcy Sustained Antigen-Specific Antitumor Recall Response Mediated by Gene-Modified CD4+ T Helper-1 and CD8+ T Cells Cancer Res., December 1, 2007; 67(23): 11428 - 11437. [Abstract] [Full Text] [PDF]

				J. Ehrchen, L. Helming, G. Varga, B. Pasche, K. Loser, M. Gunzer, C. Sunderkotter, C. Sorg, J. Roth, and A. Lengeling Vitamin D receptor signaling contributes to susceptibility to infection with Leishmania major FASEB J, October 1, 2007; 21(12): 3208 - 3218. [Abstract] [Full Text] [PDF]

				M. T. Bailey, H. Engler, N. D. Powell, D. A. Padgett, and J. F. Sheridan Repeated social defeat increases the bactericidal activity of splenic macrophages through a Toll-like receptor-dependent pathway Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1180 - R1190. [Abstract] [Full Text] [PDF]

				O. Goldmann, M. von Kockritz-Blickwede, C. Holtje, G. S. Chhatwal, R. Geffers, and E. Medina Transcriptome Analysis of Murine Macrophages in Response to Infection with Streptococcus pyogenes Reveals an Unusual Activation Program Infect. Immun., August 1, 2007; 75(8): 4148 - 4157. [Abstract] [Full Text] [PDF]

				J. C. O'Connor, C. L. Sherry, C. B. Guest, and G. G. Freund Type 2 Diabetes Impairs Insulin Receptor Substrate-2-Mediated Phosphatidylinositol 3-Kinase Activity in Primary Macrophages to Induce a State of Cytokine Resistance to IL-4 in Association with Overexpression of Suppressor of Cytokine Signaling-3 J. Immunol., June 1, 2007; 178(11): 6886 - 6893. [Abstract] [Full Text] [PDF]

				A. J. Fleetwood, T. Lawrence, J. A. Hamilton, and A. D. Cook Granulocyte-Macrophage Colony-Stimulating Factor (CSF) and Macrophage CSF-Dependent Macrophage Phenotypes Display Differences in Cytokine Profiles and Transcription Factor Activities: Implications for CSF Blockade in Inflammation J. Immunol., April 15, 2007; 178(8): 5245 - 5252. [Abstract] [Full Text] [PDF]

				D. A. Fraser, M. Arora, S. S. Bohlson, E. Lozano, and A. J. Tenner Generation of Inhibitory NF{kappa}B Complexes and Phosphorylated cAMP Response Element-binding Protein Correlates with the Anti-inflammatory Activity of Complement Protein C1q in Human Monocytes J. Biol. Chem., March 9, 2007; 282(10): 7360 - 7367. [Abstract] [Full Text] [PDF]

				L. K. Weaver, P. A. Pioli, K. Wardwell, S. N. Vogel, and P. M. Guyre Up-regulation of human monocyte CD163 upon activation of cell-surface Toll-like receptors J. Leukoc. Biol., March 1, 2007; 81(3): 663 - 671. [Abstract] [Full Text] [PDF]

				M. Puppo, M. C. Bosco, M. Federico, S. Pastorino, and L. Varesio Hypoxia inhibits Moloney murine leukemia virus expression in activated macrophages J. Leukoc. Biol., February 1, 2007; 81(2): 528 - 538. [Abstract] [Full Text] [PDF]

				S. Wehner, F. F Behrendt, B. N Lyutenski, M. Lysson, A. J Bauer, A. Hirner, and J. C Kalff Inhibition of macrophage function prevents intestinal inflammation and postoperative ileus in rodents Gut, February 1, 2007; 56(2): 176 - 185. [Abstract] [Full Text] [PDF]

				J. L. Brogdon, Y. Xu, S. J. Szabo, S. An, F. Buxton, D. Cohen, and Q. Huang Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector cell function Blood, February 1, 2007; 109(3): 1123 - 1130. [Abstract] [Full Text] [PDF]

				J. Ehrchen, L. Steinmuller, K. Barczyk, K. Tenbrock, W. Nacken, M. Eisenacher, U. Nordhues, C. Sorg, C. Sunderkotter, and J. Roth Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes Blood, February 1, 2007; 109(3): 1265 - 1274. [Abstract] [Full Text] [PDF]

				J. A. Frank, C. M. Wray, D. F. McAuley, R. Schwendener, and M. A. Matthay Alveolar macrophages contribute to alveolar barrier dysfunction in ventilator-induced lung injury Am J Physiol Lung Cell Mol Physiol, December 1, 2006; 291(6): L1191 - L1198. [Abstract] [Full Text] [PDF]

F. O. Martinez, S. Gordon, M. Locati, and A. Mantovani Transcriptional Profiling of the Human Monocyte-to-Macrophage Differentiation and Polarization: New Molecules and Patterns of Gene Expression J.