当前位置: X-MOL 学术J. Immunol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
TLR2 Dimerization Blockade Allows Generation of Homeostatic Intestinal Macrophages under Acute Colitis Challenge
The Journal of Immunology ( IF 3.6 ) Pub Date : 2019-12-27 , DOI: 10.4049/jimmunol.1900470
Mor Gross-Vered 1 , Liraz Shmuel-Galia 2 , Batya Zarmi 2 , Fiachra Humphries 3 , Christoph Thaiss 1 , Tomer-Meir Salame 4 , Eyal David 1 , Louise Chappell-Maor 1 , Katherine A Fitzgerald 3 , Yechiel Shai 5 , Steffen Jung 6
Affiliation  

Key Points TLR dimerization blockade impairs TLR2/1 and TLR2/6 signaling in macrophages. TLR2 dimer blockade ameliorates acute experimentally induced colitis. Treatment blunts monocyte activation and allows generation of tissue macrophages. Recruited blood monocytes contribute to the establishment, perpetuation, and resolution of tissue inflammation. Specifically, in the inflamed intestine, monocyte ablation was shown to ameliorate colitis scores in preclinical animal models. However, the majority of intestinal macrophages that seed the healthy gut are also monocyte derived. Monocyte ablation aimed to curb inflammation would therefore likely interfere with intestinal homeostasis. In this study, we used a TLR2 trans-membrane peptide that blocks TLR2 dimerization that is critical for TLR2/1 and TLR2/6 heterodimer signaling to blunt inflammation in a murine colitis model. We show that although the TLR2 peptide treatment ameliorated colitis, it allowed recruited monocytes to give rise to macrophages that lack the detrimental proinflammatory gene signature and reduced potentially damaging neutrophil infiltrates. Finally, we demonstrate TLR blocking activity of the peptide on in vitro cultured human monocyte-derived macrophages. Collectively, we provide a significantly improved anti-inflammatory TLR2 peptide and critical insights in its mechanism of action toward future potential use in the clinic.

中文翻译:

TLR2 二聚化阻断允许在急性结肠炎挑战下产生稳态肠道巨噬细胞

关键点 TLR 二聚化阻断会损害巨噬细胞中的 TLR2/1 和 TLR2/6 信号传导。TLR2 二聚体阻断可改善急性实验性结肠炎。治疗减弱了单核细胞的活化并允许组织巨噬细胞的产生。招募的血液单核细胞有助于组织炎症的建立、持续和消退。具体而言,在发炎的肠道中,单核细胞消融被证明可以改善临床前动物模型中的结肠炎评分。然而,在健康肠道中播种的大多数肠道巨噬细胞也是单核细胞来源的。因此,旨在抑制炎症的单核细胞消融可能会干扰肠道稳态。在这项研究中,我们使用 TLR2 跨膜肽阻断 TLR2 二聚化,这对 TLR2/1 和 TLR2/6 异源二聚体信号传导至关重要,以减轻小鼠结肠炎模型中的炎症。我们表明,虽然 TLR2 肽治疗改善了结肠炎,但它允许募集的单核细胞产生缺乏有害促炎基因特征的巨噬细胞,并减少了潜在的破坏性中性粒细胞浸润。最后,我们证明了肽对体外培养的人单核细胞衍生的巨噬细胞的 TLR 阻断活性。总的来说,我们提供了一种显着改进的抗炎 TLR2 肽,并对其作用机制提供了重要见解,以促进未来在临床中的潜在用途。它允许招募的单核细胞产生巨噬细胞,这些巨噬细胞缺乏有害的促炎基因特征,并减少了潜在的破坏性中性粒细胞浸润。最后,我们证明了肽对体外培养的人单核细胞衍生的巨噬细胞的 TLR 阻断活性。总的来说,我们提供了一种显着改进的抗炎 TLR2 肽,并对其作用机制提供了重要见解,以促进未来在临床中的潜在用途。它允许招募的单核细胞产生巨噬细胞,这些巨噬细胞缺乏有害的促炎基因特征,并减少了潜在的破坏性中性粒细胞浸润。最后,我们证明了肽对体外培养的人单核细胞衍生的巨噬细胞的 TLR 阻断活性。总的来说,我们提供了一种显着改进的抗炎 TLR2 肽,并对其作用机制提供了重要见解,以促进未来在临床中的潜在用途。
更新日期:2019-12-27
down
wechat
bug