Tickle my innards

Comment on Vidarsson et al, page 3573

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.

Vidarsson and colleagues have identified a novel role for the neonatal Fc receptor (FcRn) in promoting ingestion (phagocytosis) of IgG-opsonized bacteria by neutrophils. In these professional phagocytes, FcRn is not expressed on the cell surface, in contrast to the classic phagocytic receptors such as Fcγ 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?

FcRn is a structurally distinct receptor for IgG that is composed of a unique α-chain coupled to β2-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.

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 β2-microglobulin or in the α-chain of FcRn (both lack expression of FcRn). Further, opsonization of bacteria with mutant IgG (H435A) that binds to classic Fcγ receptors but not FcRn fails to support phagocytosis.

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 Fcγ receptors such as FcγRIIa and FcGγIIIb function in particle recognition and binding, whereas FcRn directs somewhat later stages of phagocytosis. At first consideration, this notion is at odds with experiments where non-professional phagocytic cells such as the simian kidney fibroblast cell line COS or Chinese hamster ovary (CHO) cells (that presumably do not express FcRn) are rendered efficiently phagocytic by expression of classic Fcγ receptors.¹  Additionally, the current manuscript does not identify the precise function of FcRn in the complex process of phagocytosis. Finally, there are some glaring inconsistencies in the proposed model that need to be reconciled. For example, if FcRn is not expressed on the cell surface and can only bind IgG at low pH as occurs in a more mature phagosome (the phagosome cannot acidify if it is not a closed vacuole), how can it sense and contribute to internalization of phagocytic prey? During phagocytosis, the phagosome is completely remodeled by a progressive maturation process involving fusion of the nascent phagosome with endocytic vesicles that ultimately yields a hybrid organelle, the phagolysosome.²  The latter possesses a number of degradative properties that function in concert, including a very low pH, hydrolytic enzymes for particle digestion, antimicrobial peptides, and the ability to generate toxic reactive oxidative species.³  It is possible then that signals from FcRn direct slightly later events involving membrane fusion between endosomes and the maturing phagosome. However, additional experiments will need to be conducted to reconcile these apparent discrepancies.

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 α-chain or in the closely associated β2-microglobulin? What are the signaling pathways triggered by FcRn and how exactly do they modulate the phagocytic process? In addition to the adaptor protein complex 2 as suggested by the authors, likely suspects include tyrosine kinases such as Syk, Hck, Lyn, Fgr, and Fyn, tyrosine phosphatases such as SHP-1, or lipid phosphatases such as SHIP. We will await the results of these studies with great interest.▪