B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile
B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile
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DOI：
10.1073/pnas.1215840110
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发表时间：
2013-03-26
影响因子：
11.1
通讯作者：
Nikolajczyk, Barbara S.
中科院分区：
文献类型：
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作者：
DeFuria, Jason;Belkina, Anna C.;Nikolajczyk, Barbara S.
2型糖尿病(T2D)患者存在与疾病相关的B细胞功能改变，但这些改变在疾病发病机制中所起的作用尚不清楚。这里的数据显示，肥胖小鼠的B细胞与瘦小鼠的B细胞相比，产生了促炎细胞因子。体内补充研究表明，与肥胖WT小鼠相比，肥胖B细胞缺失小鼠的全身炎症、炎性B细胞和T细胞因子、脂肪组织炎症和胰岛素抵抗(IR)都有所降低。肥胖/胰岛素抵抗B细胞缺失小鼠的炎症减少与抗炎调节T细胞(Tregs)百分比的增加有关。与肥胖的WT小鼠相比，Tregs的比例急剧下降，这与这一增加形成了鲜明对比，表明B细胞可能是T细胞功能的关键调节细胞，此前已证明T细胞在IR中发挥重要作用。我们证明了来自T2D(但不是非T2D)受试者的B细胞通过接触依赖机制支持肥胖/T2D中的促炎T细胞功能。相反，在T2D和非T2D分析中，人类单核细胞增加了促炎T细胞细胞因子。这些数据支持这一结论，即B细胞是T2D炎症的关键调节细胞，因为它们直接促进促炎T细胞功能和分泌促炎细胞因子谱。因此，B细胞是治疗T2D的潜在靶点。
Patients with type 2 diabetes (T2D) have disease-associated changes in B-cell function, but the role these changes play in disease pathogenesis is not well established. Data herein show B cells from obese mice produce a proinflammatory cytokine profile compared with B cells from lean mice. Complementary in vivo studies show that obese B cell-null mice have decreased systemic inflammation, inflammatory B-and T-cell cytokines, adipose tissue inflammation, and insulin resistance (IR) compared with obese WT mice. Reduced inflammation in obese/insulin resistant B cell-null mice associates with an increased percentage of anti-inflammatory regulatory T cells (Tregs). This increase contrasts with the sharply decreased percentage of Tregs in obese compared with lean WT mice and suggests that B cells may be critical regulators of T-cell functions previously shown to play important roles in IR. We demonstrate that B cells from T2D (but not non-T2D) subjects support proinflammatory T-cell function in obesity/T2D through contact-dependent mechanisms. In contrast, human monocytes increase proinflammatory T-cell cytokines in both T2D and non-T2D analyses. These data support the conclusion that B cells are critical regulators of inflammation in T2D due to their direct ability to promote proinflammatory T-cell function and secrete a proinflammatory cytokine profile. Thus, B cells are potential therapeutic targets for T2D.