TLR4-mediated signaling induces MMP9-dependent cleavage of B cell surface CD23.
IgE production is inversely regulated by circulating and B cell surface levels of the low affinity IgE receptor, CD23. To begin to understand physiologic determinants of CD23 expression, we analyzed effects of BCR and TLR stimulation on CD23 levels. BCR and TLR 2, 3, 4, 6, and 9 agonists induced CD23 down-modulation from the cell surface. However, among the ligands only TLR4 agonists induced transcriptional activation of CD23 and generation of significant soluble CD23. These responses were induced by LPS both in vitro and in vivo, and were seen in both murine and human B cells. LPS also induced expression of matrix metalloprotease 9 (MMP9) and failed to induce CD23 cleaving activity in MMP9(-/-) cells, thus implicating MMP9 in the LPS-induced release of CD23 from the cell surface. Finally, type 1 transitional B cells uniquely produce MMP9 in response to LPS, suggesting a mechanism wherein endotoxin induces T1 cell expression of MMP9, which mediates cleavage of CD23 on distinct, mature B cells.
Jackson
Leila
L
Department of Immunology, University of Colorado Denver School of Medicine and National Jewish Health, Denver, CO 80206, USA.
Cady
Carol T
CT
Cambier
John C
JC
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D002462:Cell Membrane / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D006868:Hydrolysis; D006967:Hypersensitivity / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000819:agonists; D017455:Receptors, IgE / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology
C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011947:Receptors, Antigen, B-Cell; D017455:Receptors, IgE; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse