Immune Complex-Driven Generation of Human Macrophages with Anti-Inflammatory and Growth-Promoting Activity.
Immune Complex-Driven Generation of Human Macrophages with Anti-Inflammatory and Growth-Promoting Activity.
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DOI：
10.4049/jimmunol.1901382
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发表时间：
2020-07-01
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影响因子：
--
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为了维持体内平衡，巨噬细胞必须能够呈现炎症或抗炎表型。为了更好地了解后者，我们在高密度免疫复合体存在的情况下，用TLR配体在体外刺激人巨噬细胞。这种刺激的组合导致了炎症介质的广泛抑制和参与组织重塑和血管生成的分子的上调。免疫复合体对TLR刺激的转录分析预测了AKT下游的激活和GSK3的抑制。因此，我们用小分子GSK3抑制剂对脂多糖刺激的人巨噬细胞进行预处理，以部分复制免疫复合体存在时刺激的调节效应。在这些细胞上观察到DC-STAMP和基质金属蛋白酶(MMPs)的上调，可能是这种调节激活状态的潜在生物标志物。为了证明这些抗炎、促进生长的巨噬细胞在人类感染性疾病中的存在，分析了麻风病患者的活检组织。这种疾病的麻风性形式以高丙种球蛋白血症和细胞免疫缺陷为特征。相对于结核样麻风皮损中的巨噬细胞，麻风皮损中含有具有调节表型的巨噬细胞，表达较高水平的DC-STAMP和较低的IL-12。因此，我们认为，Fc-γ-R在TLR刺激的巨噬细胞上的信号增加可以矛盾地促进炎症的消退，并启动对组织生长和修复至关重要的过程。它还可能导致传染病的发展。
To maintain homeostasis, macrophages must be capable of assuming either an inflammatory or an anti-inflammatory phenotype. To better understand the latter, we stimulated human macrophages in vitro with TLR ligands in the presence of high-density immune complexes. This combination of stimuli resulted in a broad suppression of inflammatory mediators and an upregulation of molecules involved in tissue remodeling and angiogenesis. Transcriptomic analysis of TLR stimulation in the presence of immune complexes predicted the downstream activation of AKT and the inhibition of GSK3. Consequently, we pretreated LPS-stimulated human macrophages with small molecule inhibitors of GSK3 to partially phenocopy the regulatory effects of stimulation in the presence of immune complexes. The upregulation of DC-STAMP and matrix metalloproteases (MMPs) was observed on these cells and may represent potential biomarkers for this regulatory activation state. To demonstrate the presence of these anti-inflammatory, growth-promoting macrophages in a human infectious disease, biopsies from patients with Leprosy (Hanseniasis) were analyzed. The lepromatous form of this disease is characterized by hypergammaglobulinemia and defective cell-mediated immunity. Lesions in lepromatous leprosy contained macrophages with a regulatory phenotype expressing higher levels of DC-STAMP and lower levels of IL-12, relative to macrophages in tuberculoid leprosy lesions. Therefore, we propose that increased signaling by FcγR cross-linking on TLR-stimulated macrophages can paradoxically promote the resolution of inflammation and initiate processes critical to tissue growth and repair. It can also contribute to infectious disease progression.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
5.6
作者：
Chiu YH;Ritchlin CT
通讯作者：
Ritchlin CT
影响因子：
5.5
作者：
Fleming, Bryan D.;Chandrasekaran, Prabha;Mosser, David M.
通讯作者：
Mosser, David M.
DOI：
10.1084/jem.186.7.1027
发表时间：
1997-10-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Crowley MT;Costello PS;Fitzer-Attas CJ;Turner M;Meng F;Lowell C;Tybulewicz VL;DeFranco AL
通讯作者：
DeFranco AL
影响因子：
5.3
作者：
Bechard, Matthew;Dalton, Stephen
通讯作者：
Dalton, Stephen