Protective and pathogenic functions of macrophage subsets

Geissmann, F. et al. Development of monocytes, macrophages, and dendritic cells. Science 327, 656–661 (2010).

Mantovani, B., Rabinovitch, M. & Nussenzweig, V. Phagocytosis of immune complexes by macrophages. Different roles of the macrophage receptor sites for complement (C3) and for immunoglobulin (IgG). J. Exp. Med. 135, 780–792 (1972).

Erwig, L. P. & Henson, P. M. Clearance of apoptotic cells by phagocytes. Cell Death Differ. 15, 243–250 (2008).

Hajishengallis, G. & Lambris, J. D. Microbial manipulation of receptor crosstalk in innate immunity. Nature Rev. Immunol. 11, 187–200 (2011).

Gordon, S. & Taylor, P. R. Monocyte and macrophage heterogeneity. Nature Rev. Immunol. 5, 953–964 (2005).

McGaha, T. L., Chen, Y., Ravishankar, B., van Rooijen, N. & Karlsson, M. C. Marginal zone macrophages suppress innate and adaptive immunity to apoptotic cells in the spleen. Blood 117, 5403–5412 (2011).

Iannacone, M. et al. Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus. Nature 465, 1079–1083 (2010).

Junt, T. et al. Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells. Nature 450, 110–114 (2007).

Geissmann, F., Gordon, S., Hume, D. A., Mowat, A. M. & Randolph, G. J. Unravelling mononuclear phagocyte heterogeneity. Nature Rev. Immunol. 10, 453–460 (2010).

Cros, J. et al. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 33, 375–386 (2010).

Sutterwala, F. S., Noel, G. J., Clynes, R. & Mosser, D. M. Selective suppression of interleukin-12 induction after macrophage receptor ligation. J. Exp. Med. 185, 1977–1985 (1997).

Sutterwala, F. S., Noel, G. J., Salgame, P. & Mosser, D. M. Reversal of proinflammatory responses by ligating the macrophage Fcγ receptor type I. J. Exp. Med. 188, 217–222 (1998).

Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nature Rev. Immunol. 8, 958–969 (2008).

Murray, P. J. & Wynn, T. A. Obstacles and opportunities for understanding macrophage polarization. J. Leukoc. Biol. 89, 557–563 (2011).

Hagemann, T. et al. “Re-educating” tumor-associated macrophages by targeting NF-κB. J. Exp. Med. 205, 1261–1268 (2008). This study shows that activation of NF-κB by IL-1R and MYD88 signalling is required to maintain the immunosuppressive function of TAMs. In the absence of NF-κB signalling, TAMs adopt a 'classically' activated phenotype and kill tumour cells.

Rutschman, R. et al. Cutting edge: Stat6-dependent substrate depletion regulates nitric oxide production. J. Immunol. 166, 2173–2177 (2001).

Kawanishi, N., Yano, H., Yokogawa, Y. & Suzuki, K. Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fat-diet-induced obese mice. Exerc. Immunol. Rev. 16, 105–118 (2010).

Mylonas, K. J., Nair, M. G., Prieto-Lafuente, L., Paape, D. & Allen, J. E. Alternatively activated macrophages elicited by helminth infection can be reprogrammed to enable microbial killing. J. Immunol. 182, 3084–3094 (2009).

Stout, R. D. et al. Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J. Immunol. 175, 342–349 (2005).

Stout, R. D. & Suttles, J. Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J. Leukoc. Biol. 76, 509–513 (2004).

Barnes, M. J. & Powrie, F. Regulatory T cells reinforce intestinal homeostasis. Immunity 31, 401–411 (2009).

Varol, C. et al. Intestinal lamina propria dendritic cell subsets have different origin and functions. Immunity 31, 502–512 (2009).

Maloy, K. J. & Powrie, F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474, 298–306 (2011).

Jenkins, S. J. et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332, 1284–1288 (2011). A study convincingly showing that tissue macrophages undergo rapid in situ proliferation in response to IL-4.

Chen, G. Y. & Nunez, G. Sterile inflammation: sensing and reacting to damage. Nature Rev. Immunol. 10, 826–837 (2010).

Matzinger, P. & Kamala, T. Tissue-based class control: the other side of tolerance. Nature Rev. Immunol. 11, 221–230 (2011).

Nish, S. & Medzhitov, R. Host defense pathways: role of redundancy and compensation in infectious disease phenotypes. Immunity 34, 629–636 (2011). An elegant exposition of the complexities associated with the understanding the host–pathogen interplay.

Borden, E. C. et al. Interferons at age 50: past, current and future impact on biomedicine. Nature Rev. Drug Discov. 6, 975–990 (2007).

Elinav, E., Strowig, T., Henao-Mejia, J. & Flavell, R. A. Regulation of the antimicrobial response by NLR proteins. Immunity 34, 665–679 (2011).

Kawai, T. & Akira, S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34, 637–650 (2011).

Osorio, F. & Reis, E. S. C. Myeloid C-type lectin receptors in pathogen recognition and host defense. Immunity 34, 651–664 (2011). A concise up-to-date summary of the role of C-type lectin receptors in pathogen-specific immune responses.

Nathan, C. & Ding, A. Nonresolving inflammation. Cell 140, 871–882 (2010).

Serbina, N. V., Jia, T., Hohl, T. M. & Pamer, E. G. Monocyte-mediated defense against microbial pathogens. Annu. Rev. Immunol. 26, 421–452 (2008).

Haile, L. A. et al. Myeloid-derived suppressor cells in inflammatory bowel disease: a new immunoregulatory pathway. Gastroenterology 135, 871–881 (2008).

Cripps, J. G. & Gorham, J. D. MDSC in autoimmunity. Int. Immunopharmacol. 11, 789–793 (2011).

Garcia, M. R. et al. Monocytic suppressive cells mediate cardiovascular transplantation tolerance in mice. J. Clin. Invest. 120, 2486–2496 (2010).

Delano, M. J. et al. MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis. J. Exp. Med. 204, 1463–1474 (2007).

Semerad, C. L., Liu, F., Gregory, A. D., Stumpf, K. & Link, D. C. G-CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood. Immunity 17, 413–423 (2002).

Semerad, C. L., Poursine-Laurent, J., Liu, F. & Link, D. C. A role for G-CSF receptor signaling in the regulation of hematopoietic cell function but not lineage commitment or differentiation. Immunity 11, 153–161 (1999).

Hanna, R. N. et al. The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C− monocytes. Nature Immunol. 12, 778–785 (2011). An important study, which identified the orphan nuclear receptor NR4A1 as a master transcription factor that regulates the differentiation and survival of 'patrolling' LY6C− monocytes.

Swirski, F. K. et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325, 612–616 (2009). This study used a series of fascinating and technically challenging experiments to define the spleen as a monocyte reservoir.

Aldridge, J. R. Jr et al. TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection. Proc. Natl Acad. Sci. USA 106, 5306–5311 (2009).

Dunay, I. R. & Sibley, L. D. Monocytes mediate mucosal immunity to Toxoplasma gondii. Curr. Opin. Immunol. 22, 461–466 (2010).

Serbina, N. V. et al. Distinct responses of human monocyte subsets to Aspergillus fumigatus conidia. J. Immunol. 183, 2678–2687 (2009).

Serbina, N. V. & Pamer, E. G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nature Immunol. 7, 311–317 (2006).

Kim, Y. G. et al. The Nod2 sensor promotes intestinal pathogen eradication via the chemokine CCL2-dependent recruitment of inflammatory monocytes. Immunity 34, 769–780 (2011).

Zhang, S., Kim, C. C., Batra, S., McKerrow, J. H. & Loke, P. Delineation of diverse macrophage activation programs in response to intracellular parasites and cytokines. PLoS Negl. Trop. Dis. 4, e648 (2010).

Goncalves, R., Zhang, X., Cohen, H., Debrabant, A. & Mosser, D. M. Platelet activation attracts a subpopulation of effector monocytes to sites of Leishmania major infection. J. Exp. Med. 208, 1253–1265 (2011). A demonstration of a complex interaction between a parasite, platelets and local stimulation of CCL2 to draw monocytes to an infection site.

Shi, C. et al. Bone marrow mesenchymal stem and progenitor cells induce monocyte emigration in response to circulating Toll-like receptor ligands. Immunity 34, 590–601 (2011).

Qian, B. Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011). A fascinating study that identifies the origin of metastasis-associated macrophages, which promote the extravasation, seeding and growth of tumour cells.

Bosschaerts, T. et al. Tip-DC development during parasitic infection is regulated by IL-10 and requires CCL2/CCR2, IFN-γ and MyD88 signaling. PLoS Pathog. 6, e1001045 (2010).

Hashimoto, D. et al. Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation. J. Exp. Med. 208, 1069–1082 (2011).

Bogunovic, M. et al. Origin of the lamina propria dendritic cell network. Immunity 31, 513–525 (2009).

Denning, T. L., Wang, Y. C., Patel, S. R., Williams, I. R. & Pulendran, B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nature Immunol. 8, 1086–1094 (2007). These authors identify an IL-10-producing population of CD11b+F4/80+CD11c− macrophages that promote the differentiation of FOXP3+ regulatory T cells and suppress T H 17 cell responses.

Zhu, B. et al. Plasticity of Ly-6Chi myeloid cells in T cell regulation. J. Immunol. 187, 2418–2432 (2011).

Aziz, A., Soucie, E., Sarrazin, S. & Sieweke, M. H. MafB/c-Maf deficiency enables self-renewal of differentiated functional macrophages. Science 326, 867–871 (2009). This study showed that the transcription factors MAF and MAFB inhibit self-renewal of functionally differentiated monocytes and macrophages.

Pesce, J. T. et al. Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. PLoS Pathog. 5, e1000371 (2009). This study identifies ARG1 as the key mediator of the suppressive function of M2 macrophages.

Serbina, N. V., Salazar-Mather, T. P., Biron, C. A., Kuziel, W. A. & Pamer, E. G. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19, 59–70 (2003).

Sindrilaru, A. et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J. Clin. Invest. 121, 985–997 (2011).

Ricardo, S. D., van Goor, H. & Eddy, A. A. Macrophage diversity in renal injury and repair. J. Clin. Invest. 118, 3522–3530 (2008).

Wynn, T. A. & Barron, L. Macrophages: master regulators of inflammation and fibrosis. Semin. Liver Dis. 30, 245–257 (2010).

Wynn, T. A. Fibrotic disease and the TH1/TH2 paradigm. Nature Rev. Immunol. 4, 583–594 (2004).

Xiao, W., Hong, H., Kawakami, Y., Lowell, C. A. & Kawakami, T. Regulation of myeloproliferation and M2 macrophage programming in mice by Lyn/Hck, SHIP, and Stat5. J. Clin. Invest. 118, 924–934 (2008).

Biswas, S. K. & Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nature Immunol. 11, 889–896 (2010).

Arnold, L. et al. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J. Exp. Med. 204, 1057–1069 (2007).

Barron, L. & Wynn, T. A. Fibrosis is regulated by Th2 and Th17 responses and by dynamic interactions between fibroblasts and macrophages. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G723–G728 (2011).

Roberts, A. B. et al. Transforming growth factor type β: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc. Natl Acad. Sci. USA 83, 4167–4171 (1986).

Sunderkotter, C., Steinbrink, K., Goebeler, M., Bhardwaj, R. & Sorg, C. Macrophages and angiogenesis. J. Leukoc. Biol. 55, 410–422 (1994).

Shimokado, K. et al. A significant part of macrophage-derived growth factor consists of at least two forms of PDGF. Cell 43, 277–286 (1985).

Wynn, T. A. Cellular and molecular mechanisms of fibrosis. J. Pathol. 214, 199–210 (2008).

Atabai, K. et al. Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages. J. Clin. Invest. 119, 3713–3722 (2009).

Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Med. 10, 942–949 (2004).

Imai, T. et al. Selective recruitment of CCR4-bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine. Int. Immunol. 11, 81–88 (1999).

Gabbiani, G. The myofibroblast in wound healing and fibrocontractive diseases. J. Pathol. 200, 500–503 (2003).

Fiorentino, D. F. et al. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J. Immunol. 146, 3444–3451 (1991).

Savage, N. D. et al. Human anti-inflammatory macrophages induce Foxp3+ GITR+ CD25+ regulatory T cells, which suppress via membrane-bound TGFβ-1. J. Immunol. 181, 2220–2226 (2008).

Herbert, D. R. et al. Arginase I suppresses IL-12/IL-23p40-driven intestinal inflammation during acute schistosomiasis. J. Immunol. 184, 6438–6446 (2010).

Sutherland, T. E., Maizels, R. M. & Allen, J. E. Chitinases and chitinase-like proteins: potential therapeutic targets for the treatment of T-helper type 2 allergies. Clin. Exp. Allergy 39, 943–955 (2009).

Pesce, J. T. et al. Retnla (Relmα/Fizz1) suppresses helminth-induced Th2-type immunity. PLoS Pathog. 5, e1000393 (2009).

Reese, T. A. et al. Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature 447, 92–96 (2007).

London, A. et al. Neuroprotection and progenitor cell renewal in the injured adult murine retina requires healing monocyte-derived macrophages. J. Exp. Med. 208, 23–39 (2011).

Odegaard, J. I. & Chawla, A. Alternative macrophage activation and metabolism. Annu. Rev. Pathol. 6, 275–297 (2011).

Lumeng, C. N., Bodzin, J. L. & Saltiel, A. R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175–184 (2007). This study, along with reference 84, shows that diet-induced obesity can lead to a shift in the activation state of adipose-associated macrophages from an M2 phenotype (induced by PPARγ) in lean animals to an M1 phenotype that contributes to insulin resistance.

Odegaard, J. I. et al. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 447, 1116–1120 (2007).

Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nature Med. 17, 179–188 (2011).

Chawla, A. et al. Macrophage-mediated inflammation in metabolic disease. Nature Rev. Immunol. 10 Oct 2011 (doi:10.1038/nri3071).

de Waal Malefyt, R. et al. Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes. Comparison with IL-4 and modulation by IFN-gamma or IL-10. J. Immunol. 151, 6370–6381 (1993).

Gordon, S. Alternative activation of macrophages. Nature Rev. Immunol. 3, 23–35 (2003).

Anthony, R. M. et al. Memory TH2 cells induce alternatively activated macrophages to mediate protection against nematode parasites. Nature Med. 12, 955–960 (2006).

Bhatia, S. et al. Rapid host defense against Aspergillus fumigatus involves alveolar macrophages with a predominance of alternatively activated phenotype. PLoS ONE 6, e15943 (2011).

Prasse, A. et al. IL-10-producing monocytes differentiate to alternatively activated macrophages and are increased in atopic patients. J. Allergy Clin. Immunol. 119, 464–471 (2007).

Kim, E. Y. et al. Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nature Med. 14, 633–640 (2008).

Nagarkar, D. R. et al. Rhinovirus infection of allergen-sensitized and -challenged mice induces eotaxin release from functionally polarized macrophages. J. Immunol. 185, 2525–2535 (2010).

Stolarski, B., Kurowska-Stolarska, M., Kewin, P., Xu, D. & Liew, F. Y. IL-33 exacerbates eosinophil-mediated airway inflammation. J. Immunol. 185, 3472–3480 (2010).

Kurowska-Stolarska, M. et al. IL-33 amplifies the polarization of alternatively activated macrophages that contribute to airway inflammation. J. Immunol. 183, 6469–6477 (2009).

van Rijt, L. S. et al. In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J. Exp. Med. 201, 981–991 (2005).

Shirey, K. A. et al. Control of RSV-induced lung injury by alternatively activated macrophages is IL-4Rα-, TLR4-, and IFN-β-dependent. Mucosal Immunol. 3, 291–300 (2010).

Nair, M. G. et al. Alternatively activated macrophage-derived RELM-α is a negative regulator of type 2 inflammation in the lung. J. Exp. Med. 206, 937–952 (2009).

Sica, A. & Bronte, V. Altered macrophage differentiation and immune dysfunction in tumor development. J. Clin. Invest. 117, 1155–1166 (2007).

Andreu, P. et al. FcRγ activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 17, 121–134 (2010).

de Visser, K. E., Korets, L. V. & Coussens, L. M. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7, 411–423 (2005).

Nardin, A. & Abastado, J. P. Macrophages and cancer. Front. Biosci. 13, 3494–3505 (2008).

Yang, X. D. et al. Histamine deficiency promotes inflammation-associated carcinogenesis through reduced myeloid maturation and accumulation of CD11b+Ly6G+ immature myeloid cells. Nature Med. 17, 87–95 (2011).

Sierra, J. R. et al. Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages. J. Exp. Med. 205, 1673–1685 (2008).

Kryczek, I. et al. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J. Exp. Med. 203, 871–881 (2006).

Imtiyaz, H. Z. et al. Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation. J. Clin. Invest. 120, 2699–2714 (2010).

Steidl, C. et al. Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. N. Engl. J. Med. 362, 875–885 (2010).

Ahn, G. O. et al. Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment. Proc. Natl Acad. Sci. USA 107, 8363–8368 (2010).

DeNardo, D. G. et al. CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16, 91–102 (2009).

Terabe, M. et al. NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R–STAT6 pathway. Nature Immunol. 1, 515–520 (2000).

Gocheva, V. et al. IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev. 24, 241–255 (2010).

Sinha, P., Clements, V. K. & Ostrand-Rosenberg, S. Interleukin-13-regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance against metastasis. Cancer Res. 65, 11743–11751 (2005).

Zorro Manrique, S. et al. Foxp3-positive macrophages display immunosuppressive properties and promote tumor growth. J. Exp. Med. 13 Jun 2011 (doi:10.1084/jem.20100730). This study identified FOXP3 expression in a subset of macrophages; this macrophage subset exhibits a distinct gene expression profile and may contribute to immunoregulation.

Duluc, D. et al. Interferon-γ reverses the immunosuppressive and protumoral properties and prevents the generation of human tumor-associated macrophages. Int. J. Cancer 125, 367–373 (2009).

Fong, C. H. et al. An antiinflammatory role for IKKβ through the inhibition of “classical” macrophage activation. J. Exp. Med. 205, 1269–1276 (2008). This study identified a new role for inhibitor of NF-κB kinase-β (IKKβ) in the regulation of macrophage activation by showing that deletion of IKKβ in the myeloid lineage confers resistance to infection with group B Streptococcus through increased production of IL-12, iNOS and MHC class II by macrophages.

Song, L. et al. Vα24-invariant NKT cells mediate antitumor activity via killing of tumor-associated macrophages. J. Clin. Invest. 119, 1524–1536 (2009).

Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

Murphy, C. A. et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med. 198, 1951–1957 (2003).

Smith, A. M. et al. Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease. J. Exp. Med. 206, 1883–1897 (2009).

Kawane, K. et al. Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443, 998–1002 (2006).

Platt, A. M., Bain, C. C., Bordon, Y., Sester, D. P. & Mowat, A. M. An independent subset of TLR expressing CCR2-dependent macrophages promotes colonic inflammation. J. Immunol. 184, 6843–6854 (2010).

Kamada, N. et al. Human CD14+ macrophages in intestinal lamina propria exhibit potent antigen-presenting ability. J. Immunol. 183, 1724–1731 (2009).

Kamada, N. et al. Unique CD14+ intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-γ axis. J. Clin. Invest. 118, 2269–2280 (2008).

Smith, P. D. et al. Intestinal macrophages and response to microbial encroachment. Mucosal Immunol. 4, 31–42 (2011).

Murai, M. et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nature Immunol. 10, 1178–1184 (2009).

Gelderman, K. A. et al. Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species. J. Clin. Invest. 117, 3020–3028 (2007).

Hendriks, J. J., Teunissen, C. E., de Vries, H. E. & Dijkstra, C. D. Macrophages and neurodegeneration. Brain Res. Brain Res. Rev. 48, 185–195 (2005).

Huang, D. R., Wang, J., Kivisakk, P., Rollins, B. J. & Ransohoff, R. M. Absence of monocyte chemoattractant protein 1 in mice leads to decreased local macrophage recruitment and antigen-specific T helper cell type 1 immune response in experimental autoimmune encephalomyelitis. J. Exp. Med. 193, 713–726 (2001).

Codarri, L. et al. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nature Immunol. 12, 560–567 (2011).

El-Behi, M. et al. The encephalitogenicity of TH17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nature Immunol. 12, 568–575 (2011).

Ponomarev, E. D., Veremeyko, T., Barteneva, N., Krichevsky, A. M. & Weiner, H. L. MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α–PU.1 pathway. Nature Med. 17, 64–70 (2011). This study identified miR-124 both as a key regulator of microglia quiescence in the central nervous system and as a previously unknown modulator of monocyte and macrophage activation.

Kiefer, R., Kieseier, B. C., Stoll, G. & Hartung, H. P. The role of macrophages in immune-mediated damage to the peripheral nervous system. Prog. Neurobiol. 64, 109–127 (2001).

Hoek, R. M. et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290, 1768–1771 (2000).

Shechter, R. et al. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med. 6, e1000113 (2009).

Woollard, K. J. & Geissmann, F. Monocytes in atherosclerosis: subsets and functions. Nature Rev. Cardiol. 7, 77–86 (2010).

Gupta, S. et al. IFN-γ potentiates atherosclerosis in ApoE knock-out mice. J. Clin. Invest. 99, 2752–2761 (1997).

Li, A. C. & Glass, C. K. The macrophage foam cell as a target for therapeutic intervention. Nature Med. 8, 1235–1242 (2002).

Febbraio, M., Hajjar, D. P. & Silverstein, R. L. CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J. Clin. Invest. 108, 785–791 (2001).

Acton, S. et al. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 271, 518–520 (1996).

Suzuki, H. et al. A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection. Nature 386, 292–296 (1997).

Pinderski, L. J. et al. Overexpression of interleukin-10 by activated T lymphocytes inhibits atherosclerosis in LDL receptor-deficient mice by altering lymphocyte and macrophage phenotypes. Circ. Res. 90, 1064–1071 (2002).

Smith, J. D. et al. Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. Proc. Natl Acad. Sci. USA 92, 8264–8268 (1995).

Stoneman, V. et al. Monocyte/macrophage suppression in CD11b diphtheria toxin receptor transgenic mice differentially affects atherogenesis and established plaques. Circ. Res. 100, 884–893 (2007).

Park, Y. M., Febbraio, M. & Silverstein, R. L. CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima. J. Clin. Invest. 119, 136–145 (2009).

Ricote, M., Li, A. C., Willson, T. M., Kelly, C. J. & Glass, C. K. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature 391, 79–82 (1998).

Erbay, E. et al. Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis. Nature Med. 15, 1383–1391 (2009).

Nagaoka, I., Trapnell, B. C. & Crystal, R. G. Upregulation of platelet-derived growth factor-A and -B gene expression in alveolar macrophages of individuals with idiopathic pulmonary fibrosis. J. Clin. Invest. 85, 2023–2027 (1990).

Nagaoka, I., Trapnell, B. C. & Crystal, R. G. Regulation of insulin-like growth factor I gene expression in the human macrophage-like cell line U937. J. Clin. Invest. 85, 448–455 (1990).

Broekelmann, T. J., Limper, A. H., Colby, T. V. & McDonald, J. A. Transforming growth factor β1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. Proc. Natl Acad. Sci. USA 88, 6642–6646 (1991).

Kolb, M., Margetts, P. J., Anthony, D. C., Pitossi, F. & Gauldie, J. Transient expression of IL-1β induces acute lung injury and chronic repair leading to pulmonary fibrosis. J. Clin. Invest. 107, 1529–1536 (2001).

Gasse, P. et al. IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice. J. Clin. Invest. 117, 3786–3799 (2007).

Wilson, M. S. et al. Bleomycin and IL-1β-mediated pulmonary fibrosis is IL-17A dependent. J. Exp. Med. 207, 535–552 (2010).

Martinez, F. O., Sica, A., Mantovani, A. & Locati, M. Macrophage activation and polarization. Front. Biosci. 13, 453–461 (2008).

Lee, C. G. et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor β1 . J. Exp. Med. 194, 809–821 (2001).

Duffield, J. S. et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56–65 (2005).

Wilson, M. S. et al. IL-13Rα2 and IL-10 coordinately suppress airway inflammation, airway-hyperreactivity, and fibrosis in mice. J. Clin. Invest. 117, 2941–2951 (2007).

Aouadi, M. et al. Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation. Nature 458, 1180–1184 (2009).

Krausgruber, T. et al. IRF5 promotes inflammatory macrophage polarization and TH1–TH17 responses. Nature Immunol. 12, 231–238 (2011). These authors show that IRF5 expression in macrophages is reversibly induced by inflammatory stimuli and contributes to the plasticity of macrophage polarization, thus identifying IRF5 as a transcriptional repressor.

Bekpen, C. et al. Death and resurrection of the human IRGM gene. PLoS Genet. 5, e1000403 (2009).

Bekpen, C., Xavier, R. J. & Eichler, E. E. Human IRGM gene “to be or not to be”. Semin. Immunopathol. 32, 437–444 (2010).

Deretic, V. Autophagy in infection. Curr. Opin. Cell Biol. 22, 252–262 (2010).

Bogdan, C. Species differences in macrophage NO production are important. Nature Immunol. 3, 102 (2002).

Fang, F. C. & Nathan, C. F. Man is not a mouse: reply. J. Leukoc. Biol. 81, 580 (2007).

Nathan, C. Role of iNOS in human host defense. Science 312, 1874–1875; author reply 1874–1875 (2006).

Manicassamy, S. et al. Activation of β-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science 329, 849–853 (2010).

Murphy, K. M. Comment on “Activation of β-catenin in dendritic cells regulates immunity versus tolerance in the intestine”. Science 333, 405; author reply 405 (2011).

Denning, T. L. et al. Functional specializations of intestinal dendritic cell and macrophage subsets that control Th17 and regulatory t cell responses are dependent on the T cell/APC ratio, source of mouse strain, and regional localization. J. Immunol. 187, 733–747 (2011).

Hume, D. A. Macrophages as APC and the dendritic cell myth. J. Immunol. 181, 5829–5835 (2008).

Asano, K. et al. CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens. Immunity 34, 85–95 (2011).

Hamann, J. et al. EMR1, the human homolog of F4/80, is an eosinophil-specific receptor. Eur. J. Immunol. 37, 2797–2802 (2007).

Liao, X. et al. Kruppel-like factor 4 regulates macrophage polarization. J. Clin. Invest. 121, 2736–2749 (2011). This paper identified Krüppel-like factor 4 (KLF4) as a crucial regulator of macrophage polarization. KLF4 cooperates with STAT6 to induce M2 and inhibit M1 macrophage activation via sequestration of co-activators required for NF-κB activation.

El Kasmi, K. C. et al. Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nature Immunol. 9, 1399–1406 (2008). These authors identify a novel TLR-dependent pathway for the induction of ARG1 expression in mouse macrophages that leads to decreased NO production and increased susceptibility to intracellular infections.

Qualls, J. E. et al. Arginine usage in mycobacteria-infected macrophages depends on autocrine-paracrine cytokine signaling. Sci. Signal. 3, ra62 (2010).

Saraiva, M. & O'Garra, A. The regulation of IL-10 production by immune cells. Nature Rev. Immunol. 10, 170–181 (2010).

Shirey, K. A., Cole, L. E., Keegan, A. D. & Vogel, S. N. Francisella tularensis live vaccine strain induces macrophage alternative activation as a survival mechanism. J. Immunol. 181, 4159–4167 (2008).

Wu, D. et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332, 243–247 (2011).