Disturbed follicular architecture in B cell A disintegrin and metalloproteinase (ADAM)10 knockouts is mediated by compensatory increases in ADAM17 and TNF-? shedding.
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ABSTRACT: 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-? signaling is critical for secondary lymphoid tissue architecture, we examined compensatory changes in ADAM17 and TNF-? in ADAM10(B-/-) B cells. Surprisingly, defective follicular development in these mice was associated with increased rather than decreased TNF-? expression. In this article, we describe an increase in TNF-? 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-? 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-? levels not seen in ADAM10(B-/-) alone. We conclude that ADAM17 overcompensation causes excessive TNF-? shedding and further upregulation of TNF-? 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-? homeostasis.
SUBMITTER: Folgosa L
PROVIDER: S-EPMC3863601 | biostudies-literature | 2013 Dec
REPOSITORIES: biostudies-literature
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