Disturbed follicular architecture in B cell A disintegrin and metalloproteinase (ADAM)10 knockouts is mediated by compensatory increases in ADAM17 and TNF-α shedding.
Disturbed follicular architecture in B cell A disintegrin and metalloproteinase (ADAM)10 knockouts is mediated by compensatory increases in ADAM17 and TNF-α shedding.
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DOI：
10.4049/jimmunol.1302042
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发表时间：
2013-12-15
期刊：
影响因子：
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通讯作者：
Conrad DH
中科院分区：
文献类型：
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作者：
Folgosa L;Zellner HB;El Shikh ME;Conrad DH
B细胞ADAM 10是发育和维持适当的次级淋巴组织结构所必需的;然而，其潜在机制尚不清楚。在这项研究中，我们发现B细胞特异性ADAM 10缺陷小鼠（ADAM 10 B −/−）的幼稚淋巴结结构紊乱，包括B/T区室化丧失、FDC网状结构减弱、胶原蛋白沉积过多和HEV形成增加。由于TNFα信号传导对次级淋巴组织结构至关重要，我们检测了ADAM 10 B −/− B细胞中ADAM 17和TNFα的代偿性变化。令人惊讶的是，这些小鼠中卵泡发育缺陷与TNFα表达增加而不是减少相关。在这里，我们描述了与WT相比，ADAM 10 B −/− B细胞中TNFα信息、mRNA稳定性、可溶性蛋白释放和膜表达的增加，这与ADAM 17信息和蛋白的增加一致。为了评估过量TNFα对ADAM 10 B −/−小鼠异常淋巴结构的机制贡献，我们进行了骨髓重建研究。仅在用ADAM 10 B −/− + TNFKO骨髓重建的辐照WT小鼠中观察到WT结构的纠正，因为在单独的ADAM 10 B −/−中未观察到TNFα水平的正常化。我们的结论是，ADAM 17过度代偿导致TNFα过度脱落和TNFα表达的进一步上调，在ADAM 10 B −/−淋巴结的B细胞皮质区域内产生异常信号环境，突出了B细胞ADAM 10和ADAM 17之间关于TNFα稳态的关键相互作用。
B cell 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 naïve lymph node architecture from B cell specific ADAM10 deficient mice (ADAM10B−/−) including loss of B/T compartmentalization, attenuation of FDC reticula, excessive collagen deposition, and increased HEV formation. Because TNFα signaling is critical for secondary lymphoid tissue architecture, we examined compensatory changes in ADAM17 and TNFα in ADAM10B−/− B cells. Surprisingly, defective follicular development in these mice was associated with increased rather than decreased TNFα expression. Here, we describe an increase in TNFα message, mRNA stability, soluble protein release, and membrane expression in ADAM10B−/− B cells compared to WT, which coincides with increased ADAM17 message and protein. To assess the mechanistic contribution of excessive TNFα to abnormal lymphoid architecture in ADAM10B−/− mice, we performed a bone marrow reconstitution study. Rectification of WT architecture was noted only in irradiated WT mice reconstituted with ADAM10B−/− + TNFKO bone marrow due to normalization of TNFα levels not seen in ADAM10B−/− alone. We conclude that ADAM17 overcompensation causes excessive TNFα shedding and further upregulation of TNFα expression, creating an aberrant signaling environment within B cell cortical regions of ADAM10B−/− lymph nodes, highlighting a key interplay between B cell ADAM10 and ADAM17 with respect to TNFα homeostasis.