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Blood, 15 November 2006, Vol. 108, No. 10, pp. 3230-3231.
Tickle my innardsUNIVERSITY OF TORONTO
The manuscript by Vidarsson and colleagues is the first description of a role for the neonatal Fc receptor (FcRn) in promoting phagocytosis of microorganisms by neutrophils. The primary site of action of FcRn is apparently not on the cell surface (as for other classical phagocytic receptors) but rather within the acidic milieu of the phagosome after ingestion. The mechanism by which FcRn mediates these important effects remains to be clarified.
FcRn is a structurally distinct receptor for IgG that is composed of a unique
The current manuscript illuminates some of these issues and provides compelling data for a role for FcRn in the phagocytosis of bacterial pathogens. The authors propose a model whereby the CH2 region of the heavy chain of IgG bound to microbial pathogens ligates FcRn on the phagosomal membrane and triggers a signaling cascade through domains within its cytosolic tail. FcRn efficiently binds IgG at low pH, a property that is ideally suited to ligand-receptor interactions in the acidic milieu of phagosomes and phagolysosomes. However, this property also raises some potential problems with the proposed model (see next paragraph). The physiologic importance of this receptor is highlighted by a phagocytic deficiency in neutrophils from mice that are deficient in either
Taken together, these observations contribute to a novel paradigm in regulation of phagocytosis, a process of fundamental importance in innate immunity. They suggest the somewhat heretical notion that classic Fc FcRn joins an emerging family of nonclassic phagocytic receptors that are expressed on or recruited to the internal membranes of phagosomes and, in this intracellular location, modulate various stages of phagocytosis including phagosome maturation, phagolysosome fusion, and intracellular killing of microbial pathogens. Other examples of this type of receptor include Toll-like receptors 2, 4, and 9 and CD36.4,5
While the primary observations in the current manuscript are compelling, several additional questions immediately spring to mind. For example, how and why is FcRn expression restricted to internal granules in neutrophils? Does FcRn participate in microbial killing in addition to internalization? Does the signaling function of FcRn reside in the References
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| Copyright © 2006 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
receptors and complement receptor 3 (CR3). Rather, FcRn is expressed within primary (azurophilic) and secondary (specific) granules in neutrophils and is transported to the developing phagosome along with the granules during phagocytosis, when the granules fuse with the phagosome. What then is FcRn doing in an intracellular (granular) compartment of mature phagocytes, and how does it modulate phagocytosis from this distant and relatively isolated refuge? 
-chain coupled to 
2-microglobulin. Intriguingly, the latter also couples with the major histocompatibility complex (MHC) class I protein that serves a vital function in antigen presentation. The function of FcRn has been best studied in nonphagocytic cells where it is expressed on the plasma membrane and functions in the internalization and transcellular uptake of IgG. For example, in syncytiotrophoblasts of the placenta, FcRn functions in maternal-fetal transport of IgG. In epithelial cells, FcRn functions in the transport of IgG across mucosal surfaces. In the vasculature, FcRn is expressed on the surface of endothelial cells where it is postulated to regulate the circulating levels of IgG. However in neutrophils, this IgG transport function of FcRn does not appear to be involved in promotion of phagocytosis. 
