Editorial: Macrophage functional phenotypes: no alternatives in dermal wound healing?

The role of cytokines in selectively amplifying the effector response of macrophages to activating ligands first became apparent circa 1980, with the publication of studies demonstrating that a “lymphokine,” later identified as IFN, enhanced the cytotoxic activity of LPS-stimulated macrophages [1]. In the early 1990s, Stein et al. [2] reported that IL-4 enhanced expression of the mannose receptor, an effect clearly distinct from the effects of IFN. Subsequent studies demonstrated that treatment of macrophages with IFNor IL-4, without an activating agent, selectively modified gene expression, resulting in a small number of nonoverlapping “signature” characteristics that distinguished the two cytokines [3]. The term “alternative phenotype” was coined to distinguish the IL-4-driven phenotype from the “classical,” IFNdriven phenotype. Over the past 15 years, the scientific literature has swelled with publications focused on defining the multitude of diverse macrophage phenotypes resulting from treatment with a variety of cytokines, hormones, and plasma factors under a variety of activating conditions. Although the impact of the activating signal has been ignored frequently, activation of macrophages polarized with IFNgenerates toxic reactive radicals, such as NO, as well as necrotizing cytokines, such as TNF. Activation of macrophages polarized with IL-4, IL-10, or glucocorticoids is more complex, but generally, the polarized macrophages produce less NO and more L-proline (arginase product) and “type 2" cytokines, such as IL-10 and TGF. The observed phenotype can vary significantly depending on the tissue source (physiological or pathological) of the macrophages, the complexity of the mixture of cytokines in the environment, and the time delay between treatment with cytokine and activating ligand [4]. During the past decade, the definition of alternative phenotype expanded or eroded (depending on perception) to include macrophage phenotypes induced by a range of factors, including IL-10, TGF, and glucocorticoids, in the presence or absence of activating ligands, apparently based on the logic that each of these overlapping phenotypes, like the IL-4-induced phenotype, was an “alternative” to the classical inflammatory phenotype (reviewed in refs. [4, 5]). In an effort to embed these macrophage phenotypes in the mainstream of immunological theory, macrophages displaying the classical phenotype were designated “M1” macrophages, corresponding to Th1 IFN-driven responses, and all other macrophage phenotypes were placed in the alternative category and designated “M2” macrophages, corresponding to Th2 responses. This correlation with T cells was a curious development given that these macrophage phenotypes were demonstrated to develop in T cell-deficient mice [6]. The M1 macrophages were attributed with cytotoxic, debriding functions in acute and chronic inflammation. The M2 macrophages were attributed with wound healing or tissue-remodeling functions [7], based largely on the expression of the alternative or M2 phenotype (elevated arginase, Fizz 1, and Ym1) in Th2driven, fibrotic, inflammatory responses and the hypothesized role of arginase in promoting tissue remodeling [3]. This M1/M2 generalization of tissue-destructive versus tissue-reparative macrophages has been generally accepted as a useful categorization of a complex cell lineage, and the ever-increasing reports of distinctive macrophage phenotypes, which do not fit into the M1 and M2 phenotypes, were considered “shades of gray” between the two polar opposites [5, 7]. In the current issue, Daley et al. [8] examine the role of IL-4 and IL-13, the prototypic type 2 cytokines defining “alternative macrophage phenotype,” in the process of dermal wound healing. Implantation of polyvinyl alcohol sponges resulted in an influx of macrophages, which initially produced significant amounts of the type 1 cytokines TNFand IL-6 but by Day 7, were producing predominantly TGF. Of particular interest was that the level of macrophage expression of dectin 1 and man-