Alternatively activated microglia and macrophages in the central nervous system
Introduction
Research on microglia has followed a similar path to that on macrophages. Microglia were identified as phagocytic cells that keep the CNS clean and, with time, their immunological potential was valued. Whereas it is relatively easy to obtain macrophages even from humans, microglial cells are not so easily obtainable. These difficulties have delayed the understanding of microglial immune-related mechanisms. For many years microglial cells were thought to acquire an active state after insult or injury to the CNS, the so-called “reactive microglia”. This active state, characterized by acquisition of an amoeboid shape and expression of pro-inflammatory factors, was considered to be detrimental for neuronal fate. Therefore, microglial activation was seen more as a problem than an advantage, and a myriad of drugs have been suggested to prevent microglial activation (Aisen, 2002, Block and Hong, 2005, Gao et al., 2003, Rock and Peterson, 2006). However, similarities between macrophages and microglia led to the suspicion that the latter might also have an alternative activation pathway that could be beneficial instead of harmful for neurons.
Polarization of macrophage activation was first associated to Th1 and Th2 responses. Both Th1 and Th2 T lymphocytes help B lymphocytes in clonal expansion and antibody production (Smith et al., 2000). However, Th1 responses produce pro-inflammatory Th1 factors, mainly interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα) and Toll-like receptor (TLR) agonists such as lipopolysaccharide (LPS), whereas interleukin (IL)-4 and IL-10 are the two main Th2 factors (Allavena et al., 2008, Chhor et al., 2013). Macrophages are phagocytic cells that in the resting state help removing pathogens and dead cells. Furthermore, macrophages may also undergo the classical M1 activation pathway that correlates with Th1 responses and contribute to inflammation. Interestingly, an alternative M2 activation pathway that correlated with Th2 responses was identified (Kodelja et al., 1998, Schebesch et al., 1997). Nevertheless, Th1 and Th2 responses are not the only modulators of macrophage and microglial polarization. The current view is that M1/M2 polarization may be also induced via interaction with other cell types like NK cells (Lapaque et al., 2009), apoptotic tumor cells (Weigert et al., 2007), adipocytes, hepatocytes or skeletal myocytes (Shen et al., 2011). Intense research in the last decade indicates that macrophage polarization is involved in airway diseases (Byers and Holtzman, 2011), metabolic disorders (Chinetti-Gbaguidi and Staels, 2011), diabetes (Espinoza-Jiménez et al., 2012), obesity-induced insulin resistance (Heilbronn and Campbell, 2008, Odegaard and Chawla, 2008), HIV-1-induced acquired immunodeficiency (Cassol et al., 2010) and tumor progression (Allavena et al., 2008, Sica et al., 2008, Jeannin et al., 2011). Moreover, a phenotypic imbalance occurs in psoriatic events (Djemadji-Oudjiel et al., 1996) and both M1 and M2 macrophages have a role in skin injury and repair (Mahdavian Delavary et al., 2011). Wound repair and inflammation is dependent on the differential angiogenic potential of M1 and M2 macrophages (Kodelja et al., 1997). Interestingly, M2 macrophages secrete factors needed for muscle regeneration (Sawano et al., 2015) and also increase the expression of factors that enhance the fibrogenic activity of fibroblasts (Song et al., 2000).
The discovery of the different macrophage/microglial subtypes was accompanied by the identification of a wide variety of phenotypic markers to detect the classical and the alternative activated states (see Table 1, Table 2). These markers include cytokines, chemokines, surface receptor proteins and metabolic enzymes that are involved in the different functions and/or acquisition of the distinct phenotypes and contribute to the pro- and anti-inflammatory effects of the M1 and M2 phenotypes respectively. Cytokines are soluble glycoproteins that modulate the innate and adaptive immune response in an autocrine/paracrine fashion (Doll et al., 2014). They bind to specific receptors that are subdivided into four major groups according to structural homologies in the extracellular domain and their signaling mechanisms (Liongue and Ward, 2007, Renauld, 2003, Ware, 2011). Chemokines constitute a large family of polypeptides characterized by four conserved cysteine residues that can be divided in the CXC, CC, CX3C and XC families (Fernandez and Lolis, 2002, Mélik-Parsadaniantz and Rostène, 2008). Produced as pro-peptides they are released as mature chemokines that specifically activate CXCR, CCR, CXCR or XCR G protein coupled receptors (GPCRs) (Laing and Secombes, 2004). It is important to take into account that the expression profile of polarized phenotypes differs among species, so that some markers are useful for murine but not for human microglial cells. For example, Ym1 and arginase 1 are expressed in murine microglial cells but their expression in human microglia is uncertain (Raes et al., 2005). A further issue is the possibility of macrophage infiltration into the CNS, where activated macrophages and resident microglia may eventually co-exist. The challenge now is to confirm whether alternative activation is neuroprotective and to find drugs favoring the M2 pathway or that guide microglial activation to proceed in the M2 neuroprotective mode. This review will focus on the phenotype, function and therapeutic possibilities of alternatively activated (or M2) microglial cells in the CNS.
Section snippets
Macrophages and alternative macrophage activation
The alternatively activated macrophage phenotype was first suspected due to the suggestion that these cells have immune suppression activity (Kennard and Zolla-Pazner, 1980, Webb and Brooks, 1980, Webb et al., 1980). These findings served as starting point for the understanding that the function of alternatively activated macrophages was quite different, even opposite, to that of classically activated cells. Modolell et al. (1995) reported that macrophages display two alternating functional
Microglia and alternative microglial activation
Known as the resident macrophages of the CNS, microglial cells contribute to the homeostasis of the brain. However, an important question arises when microglia are activated after a lesion or a neurological disease. Which activated cells come from the resident parenchymal cell population and which ones from macrophages that have infiltrated from blood and activated? At the theoretical level, a combination of M1 and M2 microglia and of M1 and M2 infiltrating macrophages may coexist at a given
Methods for studying microglial phenotype and function
Unlike macrophages that are readily available from blood samples, the study of human microglia is only possible ex vivo in tissue obtained from biopsies or post-mortem samples. In rodent models microglia may be studied in vivo in animal models of neuroinflammation or in vitro in brain slices or in primary cultures from newborn animals. To facilitate the study of some aspects of microglial activation, immortalized microglial cell lines have been also developed. Finally, macrophages from rodent
Concluding remarks and future directions
Microglia are involved in neuroinflammation but also in neurorestoration and repair. In order to utilize the neuroprotective potential of microglia, tools to guide cells to express the alternative activation M2 phenotype are crucial. To identify such tools, complementary techniques and experimental models (from cells to in vivo assays in transgenic animals and animal models of disease) are required. Pharmacokinetics is necessary to know whether a compound with good in vitro efficacy is able to
Conflict of interest
The authors declare no conflict of interests.
Acknowledgements
The authors wish to thank M.C. Sergaki and C.E. Kelly for their comments and suggestions during manuscript preparation.
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