Disturbed follicular architecture in B cell A disintegrin and metalloproteinase (ADAM)10 knockouts is mediated by compensatory increases in ADAM17 and TNF-α shedding.
B cell A disintegrin and metalloproteinase 10 (ADAM10) is required for the development and maintenance of proper secondary lymphoid tissue architecture; however, the underlying mechanism remains unclear. In this study, we show disturbances in naive lymph node architecture from B cell-specific ADAM10-deficient mice (ADAM10(B-/-)) including loss of B lymphocyte/T lymphocyte compartmentalization, attenuation of follicular dendritic cell reticula, excessive collagen deposition, and increased high endothelial venule formation. Because TNF-α signaling is critical for secondary lymphoid tissue architecture, we examined compensatory changes in ADAM17 and TNF-α in ADAM10(B-/-) B cells. Surprisingly, defective follicular development in these mice was associated with increased rather than decreased TNF-α expression. In this article, we describe an increase in TNF-α message, mRNA stability, soluble protein release, and membrane expression in ADAM10(B-/-) B cells compared with wild type (WT), which coincides with increased ADAM17 message and protein. To assess the mechanistic contribution of excessive TNF-α to abnormal lymphoid architecture in ADAM10(B-/-) mice, we performed a bone marrow reconstitution study. Rectification of WT architecture was noted only in irradiated WT mice reconstituted with ADAM10(B-/-) + TNF knockout bone marrow because of normalization of TNF-α levels not seen in ADAM10(B-/-) alone. We conclude that ADAM17 overcompensation causes excessive TNF-α shedding and further upregulation of TNF-α expression, creating an aberrant signaling environment within B cell cortical regions of ADAM10(B-/-) lymph nodes, highlighting a key interplay between B cell ADAM10 and ADAM17 with respect to TNF-α homeostasis.
Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA 23298;
Lauren
L
Folgosa
Hannah B
HB
Zellner
Mohey Eldin
ME
El Shikh
Daniel H
DH
Conrad
D051722:ADAM Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured; D020566:Dendritic Cells, Follicular / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D018858:Germinal Center / Q000378:metabolism / Q000648:ultrastructure*; D008198:Lymph Nodes / Q000378:metabolism / Q000648:ultrastructure*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020871:RNA Stability / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D011828:Radiation Chimera; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
D008565:Membrane Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse