gp49B1 deficiency is associated with increases in cytokine and chemokine production and severity of proliferative synovitis induced by anti-type II collagen mAb.
Mice with a disrupted gp49B gene, which encodes gp49B1 that is expressed on certain hematopoietic cells and has two immunoreceptor tyrosine-based inhibitory motifs (ITIM), exhibit augmented FcepsilonRI-initiated mast cell degranulation and resultant tissue edema. gp49B1-deficient (gp49B(-/-)) mice also exhibit exaggerated lipopolysaccharide (LPS)-induced intravascular neutrophil aggregation leading to cutaneous microangiopathy. To determine whether gp49B(-/-) mice exhibit elevated cytokine and chemokine levels leading to pathologic inflammation, we quantified clinical and morphologic parameters of arthritis and tissue levels of contributory mediators in gp49B(-/-) and gp49B1-sufficient (gp49B(+/+)) mice injected with anti-type II collagen monoclonal antibody (mAb) and LPS. Clinical scores for joint swelling and histological assessments of synovial thickness and cartilage matrix depletion at day 7 were significantly 2.3- to 2.5-fold greater and were more prolonged in gp49B(-/-) mice. At day 5, the amounts of IL-1beta, macrophage inflammatory protein (MIP)-1alpha, and MIP-2 were 2.1-, 2.5-, and 12-fold greater in joint extracts from gp49B(-/-) mice. A significant 2.7-fold more neutrophils infiltrated the synovium of gp49B(-/-) mice at day 7, and neutrophilia persisted with the delayed resolution of the synovitis. mAb-mediated depletion of neutrophils prevented the synovitis in both strains. Thus, gp49B1 counter-regulates the cytokine and chemokine induction and attendant neutrophilia that are all essential for synovitis and cartilage matrix depletion.
Zhou
Joseph S
JS
Department of Medicine, Harvard Medical School, Boston, USA.
Friend
Daniel S
DS
Lee
David M
DM
Li
Lin
L
Austen
K Frank
KF
Katz
Howard R
HR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D024043:Collagen Type II / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology; D008562:Membrane Glycoproteins / Q000172:deficiency*; D051379:Mice; D020556:Neutrophil Infiltration / Q000276:immunology; D011971:Receptors, Immunologic / Q000172:deficiency*; D013585:Synovitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology*
D000911:Antibodies, Monoclonal; D024043:Collagen Type II; D016207:Cytokines; C489448:Lilrb4 protein, mouse; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic