Eosinophils unleashed

In this issue of Blood, Munitz and colleagues demonstrate pronounced expression of the inhibitory receptor known as paired immunoglobulin-like receptor (PIR)–B on the surface of mouse eosinophils.

PIRs were first identified by Hayami et al¹  during a search for mouse orthologs of the F_c receptor for immunoglobulin A (IgA). PIR-A and PIR-B are not IgA receptors, but have since been characterized as orthologs of the human leukocyte immunoglobulin-like receptors (LILRs); PIR-B has 6 Ig-like domains and 4 immunoreceptor tyrosine-based inhibitory motifs (ITIMs), binds to MHC class I ligands, and typically serves to diminish cellular activation.^2,3  The finding that eosinophils express PIR-B is in and of itself not particularly surprising, as PIR-B has already been detected on the surface of mast cells, macrophages, and neutrophils. Similarly unsurprising is the finding that eosinophils isolated from PIR-B gene-deleted mice are effectively “unleashed,” and display augmented responses to the chemoattractant eotaxin-1 both in vitro and in vivo. However, rather more remarkable are the observations that eosinophils (and neutrophils) from the same PIR-B gene-deleted mice display diminished responses to the stimulatory ligand LTB4, and that eosinophil accumulation is reduced in response to chitin and thioglycolate, both stimuli that elicit chemotaxis at least in part based on responses to LTB4.

The first question is, of course: what are the molecular mechanisms underlying this original and unexpected finding? Moreover, how does a molecule with consensus-inhibitory motifs turn around and effectively augment specific cellular inflammatory responses? Is this unusual response unique to the LTB4-BLT1 ligand-receptor pair? In other words, might the PIR-B gene deletion or PIR-B functional blockade have a unique and unexpected impact on BLT1 receptor expression and/or its signal transduction response? Furthermore, there have been no published reports addressing the expression of the paired activating receptor PIR-A in mouse eosinophils, nor is there any information available on the role of PIR-A in modulating the responses of wild-type and/or PIR-B gene-deleted eosinophils to specific inflammatory stimuli.

In summary, Munitz and colleagues present an intriguing and unexpected finding, one that will certainly unleash our intellectual inhibitions as we continue to explore the role of eosinophils together with this class of immunomodulatory cell-surface receptors.