Multiple CD11c+ cells collaboratively express IL-1β to modulate stromal vascular endothelial growth factor and lymph node vascular-stromal growth.
Multiple CD11c+ cells collaboratively express IL-1β to modulate stromal vascular endothelial growth factor and lymph node vascular-stromal growth.
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DOI：
10.4049/jimmunol.1301765
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发表时间：
2014-05-01
期刊：
影响因子：
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通讯作者：
Lu TT
中科院分区：
文献类型：
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作者：
Benahmed F;Chyou S;Dasoveanu D;Chen J;Kumar V;Iwakura Y;Lu TT
自身免疫性疾病和其他淋巴增殖性疾病中的淋巴结病部分特征在于免疫母细胞和血管增殖。淋巴结脉管系统以及非血管基质隔室支持淋巴细胞功能，并且针对发炎节点中的血管基质扩张可以调节疾病中的淋巴细胞功能。 CD11c(+)细胞对于血管间质增殖和血管增殖所需的血管内皮生长因子(VEGF)的上调至关重要。然而，人们对靶向CD11c(+)细胞衍生的分子介质、相关CD11c(+)细胞的身份以及CD11c(+)细胞是否直接刺激表达VEGF的基质细胞知之甚少。在本研究中，我们发现 CD11c(+) CD11b(+) CCR2 依赖性单核细胞和 CCR7 依赖性树突状细胞表达 IL-1β。 IL-1β 阻断、放射敏感细胞中 IL-1β 缺乏以及 CCR2/CCR7 双重缺陷而非单一缺陷均会减弱免疫诱导的血管基质增殖。表达 VEGF 的 gp38(+) 基质成纤维网状细胞 (FRC) 富含 Thy1(+) 细胞，并与表达 CCL21 的 FRC 部分重叠，并且 FRC VEGF 因 IL-1β 缺乏或阻断而减弱。 IL-1β 定位于 T 区的外缘，此处 VEGF 表达细胞也富集。体外，富含IL-1β（+）细胞的CD11b（+）细胞可以直接诱导培养的gp38（+）Thy1（+）FRC上调VEGF。综上所述，这些结果表明了一种机制，即多个招募的 CD11c(+) 群体表达 IL-1β 并直接调节 FRC 功能，以帮助促进受刺激淋巴结中血管基质生长的启动。这些数据为CD11c(+)细胞如何调节淋巴结血管基质区室提供了新的见解，增加了对功能性基质亚群不断发展的理解，并提出了IL-1β阻断在预防炎症淋巴结生长中的可能用途。
Lymphadenopathy in autoimmune and other lymphoproliferative diseases is in part characterized by immunoblasts and vascular proliferation. The lymph node vasculature, along with the nonvascular stromal compartment, supports lymphocyte function, and targeting vascular-stromal expansion in inflamed nodes may modulate lymphocyte function in disease. CD11c(+) cells are essential for vascular-stromal proliferation and the upregulation of vascular endothelial growth factor (VEGF) needed for vascular proliferation. However, targetable CD11c(+) cell-derived molecular mediators, the identity of relevant CD11c(+) cells, and whether CD11c(+) cells directly stimulate VEGF-expressing stromal cells are poorly understood. In this study we show that CD11c(+) CD11b(+) CCR2-dependent monocytes and CCR7-dependent dendritic cells express IL-1β. IL-1β blockade, IL-1β deficiency in radiosensitive cells, and CCR2/CCR7 double deficiency but not single deficiency all attenuate immunization-induced vascular-stromal proliferation. gp38(+) stromal fibroblastic reticular cells (FRCs) that express VEGF are enriched for Thy1(+) cells and partially overlap with CCL21-expressing FRCs, and FRC VEGF is attenuated with IL-1β deficiency or blockade. IL-1β localizes to the outer borders of the T zone, where VEGF-expressing cells are also enriched. Ex vivo, CD11b(+) cells enriched for IL-1β(+) cells can directly induce cultured gp38(+)Thy1(+) FRCs to upregulate VEGF. Taken together, these results suggest a mechanism whereby multiple recruited CD11c(+) populations express IL-1β and directly modulate FRC function to help promote the initiation of vascular-stromal growth in stimulated lymph nodes. These data provide new insight into how CD11c(+) cells regulate the lymph node vascular-stromal compartment, add to the evolving understanding of functional stromal subsets, and suggest a possible utility for IL-1β blockade in preventing inflammatory lymph node growth.