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

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.