Negative regulation of phagocytosis in murine macrophages by the Src kinase family member, Fgr

Ingestion of opsonized pathogens by professional phagocytes results in the generation and release of microbicidal products that are essential for norm al host defense. Because these products can result in significant tissue in jury, phagocytosis must be regulated to limit damage to the host while allo wing for optimal clearance and destruction of opsonized pathogens. To pursu e negative regulation of phagocytosis, we assessed the effect of the Src ki nase family member, Fgr, on opsonin-dependent phagocytosis by mouse macroph ages. We chose Fs because it is present in high concentrations in circulati ng phagocytes but is not essential for Fc gamma receptor-mediated ingestion by mouse macrophages. Although expression of Fgr both in a macrophage cell line and in primary macrophages significantly attenuates ingestion mediate d by Fc gamma receptors and CR3, it does not affect macropinocytosis or rec eptor-mediated endocytosis. This selective effect of Fgr is independent of its tyrosine kinase function. After Fc gamma receptor cross-linking, Fgr be comes associated with the immunoreceptor tyrosine-based inhibition motif (I TIM)-containing receptor, SIRP alpha (a member of the signal-regulatory pro tein family, also known as Src homology 2 domain-containing protein tyrosin e phosphatase [SHP] substrate 1 [SHPS-1], brain immune globulin-like molecu le with tyrosine-based activation motifs [BIT], and P84) and potentiates th e association of the phosphatase SHP-1 with SIRP alpha. This association is responsible, at least in part, For decreasing positive signaling essential for optimal phagocytosis. These data demonstrate an important negative reg ulatory role for this Src kinase family member and suggest that this homeos tatic function must be overcome for optimal uptake and clearance of opsoniz ed pathogens.