Inhibition of pathologic inflammation by leukocyte Ig-like receptor B4 and related inhibitory receptors.
Leukocyte immunoglobulin (Ig)-like receptor B4 (LILRB4)(previously termed gp49B1) is a member of the Ig superfamily expressed constitutively on the surface of mast cells, neutrophils, and macrophages. LILRB4 inhibits IgE-dependent activation of mast cells in vitro through its two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that recruit the src homology domain type-2-containing tyrosine phosphatase 1 into the cell membrane. Accordingly, Lilrb4(-/-) mice exhibit greater incidence and severity of IgE- and mast cell-dependent anaphylactic inflammation compared with mice that express LILRB4. In addition, mast cell-dependent inflammation induced by the interaction of stem cell factor (SCF) with its receptor Kit is also more severe in Lilrb4(-/-) mice, indicating that the counterregulatory function of LILRB4 extends beyond inflammation induced by Fc receptors, which signal through ITIMs, to responses initiated through a receptor tyrosine kinase. Indeed, pathologic inflammatory responses induced by activation of neutrophils with lipopolysaccharide (LPS) alone or with tissue-specific autoantibodies are greatly exacerbated in Lilrb4(-/-) mice. The rapid upregulation of LILRB4 expression on neutrophils in Lilrb4(+/+) mice in response to LPS suggests it is an innate counterregulatory response designed to reduce pathologic inflammation. Nevertheless, LILRB4 also serves a similar purpose for inflammation induced by the humoral adaptive immune response that is manifested through effector cells bearing Fc receptors.
Katz
Howard R
HR
Department of Medicine, Harvard Medical School, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115, USA. hkatz@rics.bwh.harvard.edu
D000818:Animals; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D008024:Ligands; D008070:Lipopolysaccharides / Q000276:immunology; D008407:Mast Cells / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D051381:Rats; D011971:Receptors, Immunologic / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
D008024:Ligands; C489448:Lilrb4 protein, mouse; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D007073:Immunoglobulin E