Inhibition of pathologic inflammation by leukocyte Ig-like receptor B4 and related inhibitory receptors |
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Authors: | Howard R Katz |
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Institution: | Department of Medicine, Harvard Medical School, Boston, MA, USA.; Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA, USA. |
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Abstract: | Summary: 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. |
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Keywords: | mast cell inhibitory receptor inflammation IgE stem cell factor lipopolysaccharide |
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