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Editorial: Identification of in vivo markers for human polarized macrophages: a need that's finally met

Macrophages and monocytes are remarkably versatile cells with a diverse range of functions in tissue development, homeostasis, and repair. Macrophages, unlike other immune cells, are an integral part of virtually all tissues and display distinct phenotypes adapted to different tissues. This heterogeneity further extends to macrophages in the same tissue that have different locations. Adding further complexity to the heterogeneity, disease-related plasticity of tissue-resident macrophages and recruitment of monocyte-derived macrophages into tissues are linked to disease pathogenesis. Lastly, species differences in macrophage phenotype in humans, nonhuman primates and rodents, along with different disease models, further complicate phenotyping these diverse cells. Recent studies in mice have demonstrated that tissue-resident macrophage populations are of different developmental origins and have distinct renewal/ repopulation kinetics [1, 2]. Regardless of the complexity of macrophage populations within and between species in the normal and diseased host, an emerging view of developmental, phenotypic, and functional heterogeneity among tissue macrophages and among blood monocytes will likely refine our understanding of human biology and diseases, where specific macrophage subsets or subtypes play a critical role. The desire to understand this heterogeneity has brought about recent attempts to classify macrophages [3, 4]. Originally deduced from the Th1– Th2 lymphocyte paradigm, the widely accepted concept of M1–M2 polarization of macrophages has been used as a model to categorize monocyte and macrophage subsets in so many studies [5]. This phenotypic classification schema, first used with rodent macrophages in culture, is likely an overinterpretation of phenotypes that focuses on extreme cases and does not consider the dynamic nature of macrophage physiology in tissue microenvironments. With the reflection of the complexity of macrophage phenotype and function, paradoxically, there is a growing list of variations within or between the M1 and M2 macrophage subsets (e.g., M0, M1a, M1b, M1c, M2a, M2b, M2c, M2d, M3, M4, M5, Mha, and Mox) that have been worked out extensively in mice—but not in humans. However, with this caveat in mind, it remains true that the M1—M2 classification model provides a useful conceptual framework for understanding the activation and function of human macrophages and for developing macrophage-derived biomarkers of the different activation states that are specifically associated with particular human diseases. In mice, a few select markers for M1 and M2 polarization in vivo have been identified and characterized, but in humans, such markers have not (Table 1). The paper by GonzálezDomı́nguez et al. [6] in this issue describes one of the first successful attempts to identify and validate such markers within clinical specimens. The authors first evaluated in vitro CLEC5A and CD163L1 as human markers of GMCSF (M1)and M-CSF (M2)-driven polarization, respectively. They then evaluated the use of these two markers in identifying functionally distinct macrophage populations in healthy and pathologic human tissues. Specifically, they demonstrated that CD163L1 cells are major resident macrophages in healthy human nonlymphoid tissues, such as liver and colon. The authors further showed an increase in the number of CLEC5A macrophages in the colon and intestinal tissues of patients with IBD. Interestingly, unlike CD163L1, CLEC5A, a pattern recognition receptor of dengue virus, is expressed on circulating monocytes, suggesting that CLEC5A macrophages producing TNF are newly recruited monocytederived macrophages. Notably, in this paper, the appearance of a new mixed polarization phenotype expressing both CLEC5A and CD163L1 in IBD, coupled with loss of anti-inflammatory IL-10 and CD209 (dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin) expression in CD163L1 macrophages, demonstrated a phenotypic and functional switch of macrophages occurring in vivo. Adding clinical significance to the report, the authors described the differential