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Inhibition of pathologic inflammation by leukocyte Ig-like receptor B4 and related inhibitory receptors

Authors

  • Howard R. Katz

    Corresponding author
    1. Department of Medicine, Harvard Medical School, Boston, MA, USA.
    2. Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Boston, MA, USA.
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Howard R. Katz
Division of Rheumatology, Immunology and Allergy
1 Jimmy Fund Way Room 638A
Brigham and Women’s Hospital
Boston, MA 02115, USA
Tel.: +1 617 525 1307
Fax: +1 617 525 1308
E-mail: hkatz@rics.bwh.harvard.edu

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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