Prevention of lipopolysaccharide-induced microangiopathy by gp49B1: evidence for an important role for gp49B1 expression on neutrophils.
gp49B1 is expressed on mast cells and inhibits immunoglobulin E-dependent activation and inflammation in vivo. We now show that gp49B1 is expressed on neutrophils and prevents neutrophil-dependent vascular injury in response to lipopolysaccharide (LPS). The intradermal (i.d.) injection of LPS into gp49B1-null (gp49B-/-) but not gp49B1-sufficient (gp49B+/+) mice elicited macroscopic hemorrhages by 24 h, which were preceded on microscopic analyses by significantly more intravascular thrombi (consisting of neutrophils, platelets, and fibrin) that occluded venules and by more tissue neutrophils than in gp49B+/+ mice. However, there were no differences in the number of intact (nondegranulating) mast cells or the tissue levels of mediators that promote neutrophil recruitment. Hemorrhage was prevented by depleting neutrophils, blocking beta2 integrin-intercellular adhesion molecule 1 interactions, or inhibiting coagulation. These characteristics indicate that gp49B-/- mice are exquisitely sensitive to a local Shwartzman reaction (LSR) after a single i.d. injection of LPS, whereas in the classic LSR, a second exposure is required for increased beta2 integrin function, intravascular neutrophil aggregation, formation of occlusive thrombi, and hemorrhage. Moreover, LPS increased gp49B1 expression on neutrophils in vivo. The results suggest that gp49B1 suppresses the LPS-induced increase in intravascular neutrophil adhesion, thereby providing critical innate protection against a pathologic response to a bacterial component.
Zhou
Joseph S
JS
Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
Friend
Daniel S
DS
Feldweg
Anna M
AM
Daheshia
Massoud
M
Li
Lin
L
Austen
K Frank
KF
Katz
Howard R
HR
D000818:Animals; D002448:Cell Adhesion; D006470:Hemorrhage / Q000209:etiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008407:Mast Cells / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D008833:Microcirculation; D009504:Neutrophils / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism* / Q000502:physiology; D013927:Thrombosis / Q000209:etiology*; D014859:Warfarin
C489447:Gp49a protein, mouse; C489448:Lilrb4 protein, mouse; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D014859:Warfarin