A dual activation and inhibition role for the paired immunoglobulin-like receptor B in eosinophils.
The accumulation of eosinophils in inflammatory foci is a hallmark characteristic of Th2 inflammation. Nevertheless, the expression of inhibitory receptors such as paired immunoglobulin-like receptor B (PIR-B) and their function regulating eosinophil accumulation have received limited attention. We now report that Pirb was up-regulated in an eosinophil-dependent manner in the lungs of allergen-challenged and interleukin (IL)-13-overexpressing mice. Eosinophils expressed high levels of PIR-B, and Pirb(-/-) mice displayed increased gastrointestinal eosinophils. Consistent with these findings, PIR-B negatively regulated eotaxin-dependent eosinophil chemotaxis in vivo and in vitro. Surprisingly, Pirb(-/-) eosinophils and neutrophils had decreased leukotriene B4 (LTB(4))-dependent chemotactic responses in vitro. Furthermore, eosinophil accumulation was decreased in a chitin-induced model, partially dependent on LTB(4). Mechanistic analysis using a miniphosphoproteomic approach revealed that PIR-B recruits activating kinases after LTB(4) but not eotaxin stimulation. Consequently, eotaxin-activated Pirb(-/-) eosinophils displayed markedly increased extracellular signal-related kinase 1 and 2 (ERK1/2) phosphorylation, whereas LTB(4)-activated eosinophils had reduced ERK1/2 phosphorylation. We provide multiple lines of evidence supporting a model in which PIR-B displays opposing but potent regulatory functions in granulocyte activation. These data change the conventional wisdom that inhibitory receptors are restricted to inhibitory signals; we therefore propose that a single receptor can have dual functionality in distinct cell types after unique cellular signals.
Munitz
Ariel
A
Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, OH 45229, USA.
McBride
Melissa L
ML
Bernstein
Joshua S
JS
Rothenberg
Marc E
ME
D000485:Allergens / Q000276:immunology; D000818:Animals; D054413:Chemokine CCL11 / Q000378:metabolism; D054423:Chemokine CCL24 / Q000378:metabolism; D002633:Chemotaxis / Q000276:immunology; D002686:Chitin / Q000276:immunology / Q000494:pharmacology; D004804:Eosinophils / Q000276:immunology* / Q000378:metabolism; D004947:Esophagus / Q000276:immunology; D005260:Female; D041981:Gastrointestinal Tract / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology / Q000494:pharmacology; D007975:Leukotriene B4 / Q000378:metabolism; D008168:Lung / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D054397:Receptors, CCR3 / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
D000485:Allergens; C515457:Ccl11 protein, mouse; C515485:Ccl24 protein, mouse; C515351:Ccr3 protein, mouse; D054413:Chemokine CCL11; D054423:Chemokine CCL24; D018793:Interleukin-13; C105949:Pirb protein, mouse; D054397:Receptors, CCR3; D011971:Receptors, Immunologic; D002686:Chitin; D007975:Leukotriene B4; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3