Cellular Immunology 291 (2014) 1–2
Contents lists available at ScienceDirect
Cellular Immunology journal homepage: www.elsevier.com/locate/ycimm
Editorial
Editorial to Special Issue: Monocytes in Homeostasis and Disease The last two decades of investigation have resulted in significant revision of our understanding of monocyte biology, especially with regard to the role of migration and differentiation. In the last decade our understanding of monocyte egress from the bone marrow into the blood, their differentiation patterns within the blood, as well as trafficking and subsequent effector activity in tissues has undergone an exponential expansion. Notwithstanding, significant gaps, and with it significant controversy, remain. This debate continues, especially regarding the true origin of macrophage subsets during homeostasis and disease. While it is clear that during embryogenesis macrophage populations derive from the egg yolk [1–3] the long-term role of these early macrophage cells remains to be fully understood. Some studies in mice suggest that many of these resident tissue macrophage populations are long-lived and self-renewing, whereas other studies show that renewal occurs via immigrants from the bone marrow population. The dynamics of microglial homeostasis and reactivity is one area where this debate is robust. Unfortunately, studies involving microglia remain challenged by a paucity of specific markers that enable successful discrimination between microglia and macrophages; even the most common ‘‘microglial’’ markers, such as Iba-1, can be expressed by numerous CNS and non-CNS macrophage populations [4–6]. Furthermore, recent studies using nonirradiated mice have shown that different CNS inflammatory insults have significantly different impacts on overall microglial dynamics. For example, while peripheral blood monocytes appear to have little role as microglial precursors during autoimmune encephalomyelitis, [7] peripheral inflammatory monocytes clearly contribute to the microglial cell pool during viral encephalitis [8]. It is likely that this difference reflects differences in both intensity and type of inflammatory insult, especially considering the severity of the inflammation observed in the West Nile virus (WNV)infected brain compared to inflammation observed in experimental autoimmune encephalomyelitis (EAE). It should further be noted that in EAE most infiltrating monocytes differentiate into CD11c-expressing cells, whereas in the WNV-infected brain they differentiate into a more typical tissue inflammatory macrophage subset. There is also controversy regarding the role of transcription factors in microglia. For example, a recent study by, Kierdrof and colleagues reported that microgliogenesis was dependent on the transcription factors, PU.1 and interferon regulatory factor 8 (IRF8) [9]. While this work confirms previous studies showing the importance of PU.1 in microglial development [10], the described role for IRF8 in embryonic microglial cell development is at odds with its documented role in the adult mouse [11,12]. In the adult CNS, IRF8-deficient mice have normal or even slightly increased microglial cell numbers demonstrating a role for IRF8 in the downstream morphology and function of microglia in the adult http://dx.doi.org/10.1016/j.cellimm.2014.10.001 0008-8749/Ó 2014 Elsevier Inc. All rights reserved.
CNS [11,12]. Moreover, IRF8-deficiency is not associated with altered levels of PU.1 in microglia [11,12], which is consistent with the inability of IRF8-deficient mice to phenocopy PU.1 deficiency. These data in adult microglia suggest that the role of IFR8 defined by Kierdrof and colleagues in embryonic microglia is not sustained throughout life. Although Masuda and colleagues show that proliferation of adult microglia in the spinal cord is similar in WT and IRF8-deficient mice after injury [13], the dichotomy observed between embryonic and adult microglia in IRF8-deficient mice, may ‘‘washout’’ over time, as microglial proliferation and/or recruitment, contribute to the adult microglial cell pool. However, the techniques used by Kierdorf and colleagues to identify microglia may also account for this discrepancy. The data from Masuda, Horiuchu and Minten together shows that microglia in the brains of IRF8-deficient animals express significantly less Iba-1 [11–13]. Therefore, immunohistochemistry used by Kierdorf and colleagues may not adequately have identified microglia in embryonic brains from IRF8-deficient mice. Future examination of embryonic brain using other microglial-associated markers, including at least CD45, CD11b, CD115-eGFP, OX-2, F4/80, both by immunohistochemistry and flow cytometry might help to resolve this issue. However, based on these publications alone, it is clear that there is currently no single set of cellular markers that takes account of the possible permutations of tissue macrophage dynamics, and that gender, inflammatory challenge and age may separately, and presumably in combination, have a significant impact on monocyte differentiation and function. This special issue contains a collection of articles that are focused on summarizing some of the information obtained to date on monocyte development in the bone marrow, blood and tissues. Macrophages and monocytes in numerous organs, including the brain, the heart and gastrointestinal tract are discussed. From these reviews it is evident that monocytes and their associated downstream effector cells play a significant role in homeostasis, as well as driving pathology in numerous rodent models of inflammation. As such, future therapeutic strategies to control immune pathology may include ‘‘monocyte management’’ approaches that target specific monocyte subsets to promote better disease outcomes. Needless to say, continued investigation is needed to clarify some of the outstanding questions to ensure success of such strategies. References [1] F. Ginhoux, M. Greter, M. Leboeuf, et al, Fate mapping analysis reveals that adult microglia derive from primitive macrophages, Science 330 (2010) 841– 845. [2] S. Yona, K.W. Kim, Y. Wolf, et al, Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis, Immunity 38 (2013) 79–91.
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Editorial / Cellular Immunology 291 (2014) 1–2
[3] C. Schulz, E. Gomez Perdiguero, L. Chorro, et al, A lineage of myeloid cells independent of Myb and hematopoietic stem cells, Science 336 (2012) 86–90. [4] H.M. Golbar, T. Izawa, V. Juniantito, et al, Immunohistochemical characterization of macrophages and myofibroblasts in fibrotic liver lesions due to Fasciola infection in cattle, J. Vet. Med. Sci. 75 (2013) 857–865. [5] S. Lee, J. Zhang, Heterogeneity of macrophages in injured trigeminal nerves: cytokine/chemokine expressing vs. phagocytic macrophages, Brain Behav. Immun. 26 (2012) 891–903. [6] B.H. Ton, Q. Chen, G. Gaina, et al, Activation profile of dorsal root ganglia Iba-1 (+) macrophages varies with the type of lesion in rats, Acta Histochem. 115 (2013) 840–850. [7] B. Ajami, J.L. Bennett, C. Krieger, et al, Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool, Nat. Neurosci. 14 (2011) 1142–1149. [8] D.R. Getts, R.L. Terry, M.T. Getts, et al, Ly6c+ ‘‘inflammatory monocytes’’ are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis, J. Exp. Med. 205 (2008) 2319–2337. [9] K. Kierdorf, D. Erny, T. Goldmann, et al, Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways, Nat. Neurosci. 16 (2013) 273–280.
[10] D.R. Beers, J.S. Henkel, Q. Xiao, et al, Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis, Proc. Natl. Acad. Sci. U.S.A. 103 (2006) 16021–16026. [11] M. Horiuchi, K. Wakayama, A. Itoh, et al, Interferon regulatory factor 8/ interferon consensus sequence binding protein is a critical transcription factor for the physiological phenotype of microglia, J. Neuroinflammation 9 (2012) 227. [12] C. Minten, R. Terry, C. Deffrasnes, et al, IFN regulatory factor 8 is a key constitutive determinant of the morphological and molecular properties of microglia in the CNS, PLoS One 7 (2012) e49851. [13] T. Masuda, M. Tsuda, R. Yoshinaga, et al, IRF8 is a critical transcription factor for transforming microglia into a reactive phenotype, Cell Rep. 1 (2012) 334– 340.
Guest Editor Daniel R. Getts Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
Contents lists available at ScienceDirect
Cellular Immunology journal homepage: www.elsevier.com/locate/ycimm
Editorial
Editorial to Special Issue: Monocytes in Homeostasis and Disease The last two decades of investigation have resulted in significant revision of our understanding of monocyte biology, especially with regard to the role of migration and differentiation. In the last decade our understanding of monocyte egress from the bone marrow into the blood, their differentiation patterns within the blood, as well as trafficking and subsequent effector activity in tissues has undergone an exponential expansion. Notwithstanding, significant gaps, and with it significant controversy, remain. This debate continues, especially regarding the true origin of macrophage subsets during homeostasis and disease. While it is clear that during embryogenesis macrophage populations derive from the egg yolk [1–3] the long-term role of these early macrophage cells remains to be fully understood. Some studies in mice suggest that many of these resident tissue macrophage populations are long-lived and self-renewing, whereas other studies show that renewal occurs via immigrants from the bone marrow population. The dynamics of microglial homeostasis and reactivity is one area where this debate is robust. Unfortunately, studies involving microglia remain challenged by a paucity of specific markers that enable successful discrimination between microglia and macrophages; even the most common ‘‘microglial’’ markers, such as Iba-1, can be expressed by numerous CNS and non-CNS macrophage populations [4–6]. Furthermore, recent studies using nonirradiated mice have shown that different CNS inflammatory insults have significantly different impacts on overall microglial dynamics. For example, while peripheral blood monocytes appear to have little role as microglial precursors during autoimmune encephalomyelitis, [7] peripheral inflammatory monocytes clearly contribute to the microglial cell pool during viral encephalitis [8]. It is likely that this difference reflects differences in both intensity and type of inflammatory insult, especially considering the severity of the inflammation observed in the West Nile virus (WNV)infected brain compared to inflammation observed in experimental autoimmune encephalomyelitis (EAE). It should further be noted that in EAE most infiltrating monocytes differentiate into CD11c-expressing cells, whereas in the WNV-infected brain they differentiate into a more typical tissue inflammatory macrophage subset. There is also controversy regarding the role of transcription factors in microglia. For example, a recent study by, Kierdrof and colleagues reported that microgliogenesis was dependent on the transcription factors, PU.1 and interferon regulatory factor 8 (IRF8) [9]. While this work confirms previous studies showing the importance of PU.1 in microglial development [10], the described role for IRF8 in embryonic microglial cell development is at odds with its documented role in the adult mouse [11,12]. In the adult CNS, IRF8-deficient mice have normal or even slightly increased microglial cell numbers demonstrating a role for IRF8 in the downstream morphology and function of microglia in the adult http://dx.doi.org/10.1016/j.cellimm.2014.10.001 0008-8749/Ó 2014 Elsevier Inc. All rights reserved.
CNS [11,12]. Moreover, IRF8-deficiency is not associated with altered levels of PU.1 in microglia [11,12], which is consistent with the inability of IRF8-deficient mice to phenocopy PU.1 deficiency. These data in adult microglia suggest that the role of IFR8 defined by Kierdrof and colleagues in embryonic microglia is not sustained throughout life. Although Masuda and colleagues show that proliferation of adult microglia in the spinal cord is similar in WT and IRF8-deficient mice after injury [13], the dichotomy observed between embryonic and adult microglia in IRF8-deficient mice, may ‘‘washout’’ over time, as microglial proliferation and/or recruitment, contribute to the adult microglial cell pool. However, the techniques used by Kierdorf and colleagues to identify microglia may also account for this discrepancy. The data from Masuda, Horiuchu and Minten together shows that microglia in the brains of IRF8-deficient animals express significantly less Iba-1 [11–13]. Therefore, immunohistochemistry used by Kierdorf and colleagues may not adequately have identified microglia in embryonic brains from IRF8-deficient mice. Future examination of embryonic brain using other microglial-associated markers, including at least CD45, CD11b, CD115-eGFP, OX-2, F4/80, both by immunohistochemistry and flow cytometry might help to resolve this issue. However, based on these publications alone, it is clear that there is currently no single set of cellular markers that takes account of the possible permutations of tissue macrophage dynamics, and that gender, inflammatory challenge and age may separately, and presumably in combination, have a significant impact on monocyte differentiation and function. This special issue contains a collection of articles that are focused on summarizing some of the information obtained to date on monocyte development in the bone marrow, blood and tissues. Macrophages and monocytes in numerous organs, including the brain, the heart and gastrointestinal tract are discussed. From these reviews it is evident that monocytes and their associated downstream effector cells play a significant role in homeostasis, as well as driving pathology in numerous rodent models of inflammation. As such, future therapeutic strategies to control immune pathology may include ‘‘monocyte management’’ approaches that target specific monocyte subsets to promote better disease outcomes. Needless to say, continued investigation is needed to clarify some of the outstanding questions to ensure success of such strategies. References [1] F. Ginhoux, M. Greter, M. Leboeuf, et al, Fate mapping analysis reveals that adult microglia derive from primitive macrophages, Science 330 (2010) 841– 845. [2] S. Yona, K.W. Kim, Y. Wolf, et al, Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis, Immunity 38 (2013) 79–91.
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Editorial / Cellular Immunology 291 (2014) 1–2
[3] C. Schulz, E. Gomez Perdiguero, L. Chorro, et al, A lineage of myeloid cells independent of Myb and hematopoietic stem cells, Science 336 (2012) 86–90. [4] H.M. Golbar, T. Izawa, V. Juniantito, et al, Immunohistochemical characterization of macrophages and myofibroblasts in fibrotic liver lesions due to Fasciola infection in cattle, J. Vet. Med. Sci. 75 (2013) 857–865. [5] S. Lee, J. Zhang, Heterogeneity of macrophages in injured trigeminal nerves: cytokine/chemokine expressing vs. phagocytic macrophages, Brain Behav. Immun. 26 (2012) 891–903. [6] B.H. Ton, Q. Chen, G. Gaina, et al, Activation profile of dorsal root ganglia Iba-1 (+) macrophages varies with the type of lesion in rats, Acta Histochem. 115 (2013) 840–850. [7] B. Ajami, J.L. Bennett, C. Krieger, et al, Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool, Nat. Neurosci. 14 (2011) 1142–1149. [8] D.R. Getts, R.L. Terry, M.T. Getts, et al, Ly6c+ ‘‘inflammatory monocytes’’ are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis, J. Exp. Med. 205 (2008) 2319–2337. [9] K. Kierdorf, D. Erny, T. Goldmann, et al, Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways, Nat. Neurosci. 16 (2013) 273–280.
[10] D.R. Beers, J.S. Henkel, Q. Xiao, et al, Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis, Proc. Natl. Acad. Sci. U.S.A. 103 (2006) 16021–16026. [11] M. Horiuchi, K. Wakayama, A. Itoh, et al, Interferon regulatory factor 8/ interferon consensus sequence binding protein is a critical transcription factor for the physiological phenotype of microglia, J. Neuroinflammation 9 (2012) 227. [12] C. Minten, R. Terry, C. Deffrasnes, et al, IFN regulatory factor 8 is a key constitutive determinant of the morphological and molecular properties of microglia in the CNS, PLoS One 7 (2012) e49851. [13] T. Masuda, M. Tsuda, R. Yoshinaga, et al, IRF8 is a critical transcription factor for transforming microglia into a reactive phenotype, Cell Rep. 1 (2012) 334– 340.
Guest Editor Daniel R. Getts Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
