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2 Department of Pathology, Harvard Medical School, and Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115
Address correspondence to Howard R. Katz, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, 1 Jimmy Fund Way, Room 638A, Boston, MA 02115. Phone: (617) 525-1307; Fax: (617) 525-1308; email: hrkatz{at}mbcrr.harvard.edu
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 ß2 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 ß2 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.
Key Words: Shwartzman reaction • thrombosis • hemorrhage • cell adhesion molecules • innate immunity
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