| First Author | Folgosa L | Year | 2013 |
| Journal | J Immunol | Volume | 191 |
| Issue | 12 | Pages | 5951-8 |
| PubMed ID | 24227779 | Mgi Jnum | J:207127 |
| Mgi Id | MGI:5554492 | Doi | 10.4049/jimmunol.1302042 |
| Citation | Folgosa L, et al. (2013) Disturbed follicular architecture in B cell A disintegrin and metalloproteinase (ADAM)10 knockouts is mediated by compensatory increases in ADAM17 and TNF-alpha shedding. J Immunol 191(12):5951-8 |
| abstractText | 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-alpha signaling is critical for secondary lymphoid tissue architecture, we examined compensatory changes in ADAM17 and TNF-alpha in ADAM10(B-/-) B cells. Surprisingly, defective follicular development in these mice was associated with increased rather than decreased TNF-alpha expression. In this article, we describe an increase in TNF-alpha 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-alpha 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-alpha levels not seen in ADAM10(B-/-) alone. We conclude that ADAM17 overcompensation causes excessive TNF-alpha shedding and further upregulation of TNF-alpha 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-alpha homeostasis. |
