Heterogeneity of the macrophage lineage has long been recognized and, in part, is a result of the specialization of tissue macrophages in particular microenvironments. Circulating monocytes give rise to mature macrophages and are also heterogeneous themselves, although the physiological relevance of this is not completely understood. However, as we discuss here, recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues. These advances in our understanding have implications for the development of therapeutic strategies that are targeted to modify particular subpopulations of monocytes.

Tissue-resident macrophages are a heterogeneous population of immune cells that fulfill tissue-specific and niche-specific functions. These range from dedicated homeostatic functions, such as clearance of cellular debris and iron processing, to central roles in tissue immune surveillance, response to infection and the resolution of inflammation. Recent studies highlight marked heterogeneity in the origins of tissue macrophages that arise from hematopoietic versus self-renewing embryo-derived populations. We discuss the tissue niche-specific factors that dictate cell phenotype, the definition of which will allow new strategies to promote the restoration of tissue homeostasis. Understanding the mechanisms that dictate tissue macrophage heterogeneity should explain why simplified models of macrophage activation do not explain the extent of heterogeneity seen in vivo.

Abstractβ-Glucan is one of the most abundant polysaccharides in fungal pathogens, yet its importance in antifungal immunity is unclear. Here we show that deficiency of dectin-1, the myeloid receptor for β-glucan, rendered mice susceptible to infection with Candida albicans. Dectin-1-deficient leukocytes demonstrated significantly impaired responses to fungi even in the presence of opsonins. Impaired leukocyte responses were manifested in vivo by reduced inflammatory cell recruitment after fungal infection, resulting in substantially increased fungal burdens and enhanced fungal dissemination. Our results establish a fundamental function for β-glucan recognition by dectin-1 in antifungal immunity and demonstrate a signaling non-Toll-like patternrecognition receptor required for the induction of protective immune responses.Infections with normally nonpathogenic fungi such as Candida albicans are an emerging problem resulting from modern medical interventions and the increasing prevalence of acquired immunodeficiency1. The high incidence of morbidity and mortality associated with such diseases, especially once the fungus has disseminated, demonstrates deficiencies in both present antifungal therapies and understanding of the host immune response. Protection against such organisms is mediated mainly by phagocytic cells that recognize, ingest and kill the invading pathogen, inducing a T helper type 1 immune response, which in turn activates fungicidal effector mechanisms, such as the respiratory burst1. Although cells such as neutrophils and macrophages are thought to be crucial in that process, the mechanism underlying the recognition and initiation of the protective responses to these pathogens remains unclear. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. Europe PMC Funders GroupAuthor Manuscript Nat Immunol. Author manuscript; available in PMC 2007 July 01. Published The cell walls of fungi consist mainly of carbohydrates, including mannose-based structures (the mannoproteins), β-glucan and chitin. For immune systems of infected hosts, such polysaccharides serve as pathogen-associated molecular patterns (PAMPs) that can be recognized by a variety of host-expressed pattern-recognition receptors, including the Tolllike receptors (TLRs), although the precise functions of each of the myriad receptors that can respond to these pathogens and contribute to the induction of protective responses have not been fully elucidated.Historically, the cell walls of fungi were shown to be covered by a layer of mannoproteins, which prompted much interest in mannose-based recognition systems2. Subsequent evidence has suggested that this model may be too simplistic and that other PAMPs, particularly β-glucans, are exposed on the cell surface and therefore are potentially important in immune recognition3. In fungi such as C. albicans and Saccharomyces cerevisiae, β-glucans can comprise up to 50% of the dry weight of the fungal cell wall and are essential structural components that ...

Macrophages express a broad range of plasma membrane receptors that mediate their interactions with natural and altered-self components of the host as well as a range of microorganisms. Recognition is followed by surface changes, uptake, signaling, and altered gene expression, contributing to homeostasis, host defense, innate effector mechanisms, and the induction of acquired immunity. This review covers recent studies of selected families of structurally defined molecules, studies that have improved understanding of ligand discrimination in the absence of opsonins and differential responses by macrophages and related myeloid cells.

Zymosan is a β-glucan– and mannan-rich particle that is widely used as a cellular activator for examining the numerous responses effected by phagocytes. The macrophage mannose receptor (MR) and complement receptor 3 (CR3) have historically been considered the major macrophage lectins involved in the nonopsonic recognition of these yeast-derived particles. Using specific carbohydrate inhibitors, we show that a β-glucan receptor, but not the MR, is a predominant receptor involved in this process. Furthermore, nonopsonic zymosan binding was unaffected by genetic CD11b deficiency or a blocking monoclonal antibody (mAb) against CR3, demonstrating that CR3 was not the β-glucan receptor mediating this activity. To address the role of the recently described β-glucan receptor, Dectin-1, we generated a novel anti–Dectin-1 mAb, 2A11. Using this mAb, we show here that Dectin-1 was almost exclusively responsible for the β-glucan–dependent, nonopsonic recognition of zymosan by primary macro-phages. These findings define Dectin-1 as the leukocyte β-glucan receptor, first described over 50 years ago, and resolves the long-standing controversy regarding the identity of this important molecule. Furthermore, these results identify Dectin-1 as a new target for examining the immunomodulatory properties of β-glucans for therapeutic drug design.