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Reconsideration of Macrophage and Dendritic Cell Classification ANTICANCER RESEARCH 32: 2257-2262 (2012) Short Review Reconsideration of Macrophage and Dendritic Cell Classification TAKESHI KADOWAKI1, MISATO SHIMADA1, HIROYUKI INAGAWA1,2,3, CHIE KOHCHI1,2, MITSUOMI HIRASHIMA1 and GEN-ICHIRO SOMA1,3,4 1Faculty of Medicine, Kagawa University, Kagawa, Japan; 2Macrophi Inc., Hayashi-cho, Takamatsu-shi, Kagawa-ken, Japan; 3Institute for Drug Delivery Systems, Tokyo University of Science, Chiba, Japan; 4Institute for Health and Sciences, Tokushima Bunri University, Nishihama, Tokushima, Japan Abstract. It is well known that the activation of innate Macrophages are dynamic and heterogeneous cells that immune cells, especially antigen-presenting cells such as exhibit different roles through their cytokine production and macrophages and dendritic cells, can ameliorate or presentation of microbial components. Currently, monocytes exacerbate various diseases, including cancer. Currently, the and macrophages are divided into several groups: myeloid- macrophages and dendritic cells are categorized into several derived suppressor cells (MDSCs), M1 macrophages groups by their cell surface and intracellular molecules. (classically activated), M2 macrophages (alternatively However, the detailed classification of the differences activated) and regulatory macrophages (Mreg) (1, 2). They between macrophages and dendritic cells has still not been have also been classified on the basis of cell surface markers, established. Here, we summarized and reviewed the previous cytokine production, expression of transcription factors and studies on the classification of macrophages and dendritic their effects on other cells (1-3). cells. In addition, the previous classification of monocytes, It is well known that the differentiation of tumour- macrophages and dendritic cells is discussed based on our associated macrophages (TAMs) and MDSCs are associated findings of macrophage activation, which has both with proteins derived from tumour cells such as macrophage conventional and plasmacytoid dendritic cell phenotype. colony stimulating factor (M-CSF), granulocyte macrophage- colony stimulating factor (GM-CSF) and vascular endothelial Categorization of Monocyte and growth factor (VEGF). These proteins can induce the Macrophage Subsets expansion and accumulation of TAMs and MDSCs in tumour lesions and may also accelerate tumour growth by Macrophages play crucial roles as sentinels in first-line alerts immunosuppressive activities. Some groups have suggested against pathogens and as mediators of host defence. In that these characteristics of TAMs should categorize them as addition, they assist in maintaining homeostasis through M2 macrophages or Mregs (2, 4-6). MDSCs, which express immune regulation, by eliminating foreign substances and the myeloid lineage markers CD11b and Granulocyte- unwanted apoptotic cells. Although macrophages are found differentiation antigen-1 (Gr-1) on their surfaces and include in virtually all tissues, these cells display remarkable granulocyte and monocyte lineage cells, are a heterogeneous plasticity that allow them to efficiently respond to various population of cells that expand during cancer, inflammation environmental signals and change their phenotype. and infection, and that have a remarkable ability to suppress T-cell responses (7-9). Unfortunately, the differences between TAMs and MDSCs are not clear because the detailed definition of what Correspondence to: Gen-Ichiro Soma, Institute for Health Sciences, comprises a TAM is still obscure. Tokushima Bunri University, Nishihama, Yamashiro-cho, Usually, macrophages that are differentiated in vitro due Tokushimashi, 770-8514, Japan. Tel: +81 886028103, Fax: +81 886028103, e-mail: [email protected] to the actions of M-CSF or GM-CSF are designated as either M2 macrophages or M1 macrophages, respectively (10, 11). Key Words: Macrophage, dendritic cell, marker, classification, pDC, In fact, we confirmed that the basal expression levels of review. interleukin (IL)-10 and arginase I mRNA in macrophages 0250-7005/2012 $2.00+.40 2257 ANTICANCER RESEARCH 32: 2257-2262 (2012) Figure 1. Basal cytokines, inducible nitric oxide synthase (iNOS) and arginase (arg I) mRNA expression in macrophages differentiated with macrophage-colony stimulating factor (M-CSF, I) and granulocyte macrophage-colony stimulating factor (GM-CSF, I). Bone marrow derived mononuclear cells were cultured in the presence of M-CSF and GM-CSF for seven days according to previous reports (11, 13) with slight modifications. Total RNA of the cells was extracted and reverse transcripted using a commercial kit. The obtained cDNA was used as template for real-time quantitative PCR. The expression levels of each RNA were normalized to that of β2 microglobulin. Results are means±SEM in tripricate experiments. For statistical comparison, Student’s t-test was performed. *p<0.05, NS: not significant, IL: interleukin, TNF: tumour necrosis factor. that were differentiated with M-CSF were higher than in Categorization of Dendritic Cell Subsets macrophages that were differentiated with GM-CSF in vitro (Figure 1). By comparison, the basal expression level of Dendritic cells (DCs) are well known antigen presenting inflammatory cytokines mRNA such as IL-1β and IL-12, and cells that express MHC class II and CD86. Currently, DCs inducible nitric oxide synthase (iNOS), in macrophages are divided into two main groups: myeloid DCs (mDCs, also differentiated with GM-CSF were higher than those in known as DC-1 or classical DCs cDCs) and plasmacytoid macrophages differentiated with M-CSF. Thus, these results DCs (DC-2, pDCs). mDCs express the cell surface markers suggest that it is reasonable to apply the categorizations of CD11c and do not express B220. In addition, mDCs are also M1 and M2 macrophages in this case. divided into several groups: lymphoid organ resident DCs, When focusing on their cell surface molecule expression, interstitial DCs and monocyte-derived DCs. macrophages that were differentiated with either GM-CSF or Immature mDCs are usually differentiated with GM-CSF M-CSF expressed CD11b and F4/80, which are used as and IL-4 in vitro (14), and these immature DCs are known macrophage markers except for intestinal macrophages (12) to mature after stimulation with agents such as tumor (Figure 2A). In addition, major histocompatibility complex necrosis factor-α (TNF-α), LPS, and other immune class II (MHC class II, I-A/I-E) expression on macrophages stimulators (15, 16). The confirmation of DCs is usually differentiated with GM-CSF was higher than on based on the type of inflammatory cytokines production, macrophages differentiated with M-CSF (Figure 2B). Based such as IL-12, and the expression of cell surface markers, on previous studies, those macrophages differentiated with such as CD80, CD86 and MHC class II molecules. As GM-CSF and M-CSF undoubtedly could be defined as mentioned above, macrophages can also be differentiated macrophages, whereas the macrophages differentiated with with GM-CSF (i.e. categorized as M1 macrophages). In M-CSF expressed Ly-6C, which belongs to Gr-1. In addition, addition, in our experiments, macrophages differentiated Ly-6C expression was up-regulated by lipopolysaccharide with GM-CSF expressed CD11b, F4/80, CD11c and MHC (LPS) and co-culture with tumour cells (13). If M2 class II molecules on their surfaces (Figure 2A and B and macrophages belong to a category that is different from Figure 3). Therefore, it is possible that macrophages MDSCs, then M2 macrophages, such as TAMs, can possibly differentiated with GM-CSF and immature DCs (or DCs) change their phenotype to MDSCs under certain have partly similar characteristics. However, differences physiological conditions. This suggests that the differences between macrophages differentiated with GM-CSF and DCs between TAMs and MDSCs cannot be defined based on their have not been reported previously. This has led us to surface marker expressions. hypothesize that immature DCs (or DCs) are one type of 2258 Kadowaki et al: Classification of Macrophage and Dendritic Cell (Review) were also differentiated with a high concentration of GM- CSF (17). Therefore, it is possible that macrophages differentiated with GM-CSF or immature DCs are easily changed to an MDSC phenotype. It is well known that the surface marker profile that defines pDCs is B220+ CD11c+ or intermediate, Ly-6C+ and plasmacytoid dendritic cell antigen 1+ (PDCA-1+). Immature pDCs also express toll like receptor (TLR)7 or TLR9 and produce type I interferons (IFNs), such as IFN-α and IFN- β, via myeloid differentiation factor 88 (MyD88) and interferon regulatory factor (IRF) 7 signalling cascade (18, 19). The functional roles of type I IFNs are the activation of CD8+ T- and natural killer (NK) cells and the induction of Th1 response (20-22). In contrast, mature pDCs reduce production of type I IFNs, which also leads to immune tolerogenic activity, such as inducing the production of IL- 10 by CD8+ T-cells and Tregs, or inducing Th2 responses (23). Therefore, pDCs play crucial roles linking the innate and adaptive arms of the immune system. Recently, many investigators have reported the frequency of pDCs in various diseases. Although pDCs classically belong to the lymphoid lineage, they are currently defined as a subset of DCs derived from both myeloid and lymphoid precursors (24). We also confirmed the frequency of pDCs in tumour-bearing mice. CD11c+ PDCA-1+ cells infiltrated into Figure 2. Flow cytometry analyses of macrophages differentiated
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