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体外脓毒症上调人 T 细胞而非 B 细胞上的孤啡肽/NociceptinFQ 受体表达和功能。

In vitro sepsis up-regulates Nociceptin/Orphanin FQ receptor expression and function on human T- but not B-cells.

机构信息

Department of Cardiovascular Sciences, Anaesthesia, Critical Care and Pain Management, University of Leicester, Leicester, UK.

Cellomatics Biosciences Ltd, Nottingham, UK.

出版信息

Br J Pharmacol. 2023 Sep;180(17):2298-2314. doi: 10.1111/bph.16088. Epub 2023 May 11.

DOI:10.1111/bph.16088
PMID:37021779
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10953342/
Abstract

BACKGROUND AND PURPOSE

In animal models of sepsis, increased activation of the Nociceptin/Orphanin FQ (N/OFQ) receptor NOP is associated with mortality and NOP antagonists improved survival. We have explored the role of the N/OFQ-NOP system in freshly isolated volunteer human B- and T-cells incubated with lipopolysaccharide (LPS) and peptidoglycan G (PepG) as a model of in vitro sepsis.

EXPERIMENTAL APPROACH

B- and T-cell NOP expression was measured using the NOP fluorescent probe N/OFQ , N/OFQ content was measured using immunofluorescence, N/OFQ release was tracked using a CHO biosensor assay and NOP function was measured using transwell migration and cytokine/chemokine release using a 25-plex assay format. Cells were challenged with LPS/PepG.

KEY RESULTS

CD19-positive B-cells bound N/OFQ ; they also contain N/OFQ. Stimulation with CXCL13/IL-4 increased N/OFQ release. N/OFQ trended to reduced migration to CXCL13/IL-4. Surface NOP expression was unaffected by LPS/PepG, but this treatment increased GM-CSF release in an N/OFQ sensitive manner. CD3-positive T-cells did not bind N/OFQ ; they did contain N/OFQ. Stimulation with CXCL12/IL-6 increased N/OFQ release. When incubated with LPS/PepG, NOP surface expression was induced leading to N/OFQ binding. In LPS/PepG-treated cells, N/OFQ reduced migration to CXCL12/IL-6. LPS/PepG increased GM-CSF release in an N/OFQ sensitive manner.

CONCLUSIONS AND IMPLICATIONS

We suggest both a constitutive and sepsis-inducible N/OFQ-NOP receptor autocrine regulation of B- and T-cell function, respectively. These NOP receptors variably inhibit migration and reduce GM-CSF release. These data provide mechanistic insights to the detrimental role for increased N/OFQ signalling in sepsis and suggest a potential role for NOP antagonists as treatments.

摘要

背景与目的

在脓毒症动物模型中，孤啡肽/孤啡肽受体 NOP 的过度激活与死亡率相关，而 NOP 拮抗剂可提高存活率。我们已经探索了孤啡肽-NOP 系统在新鲜分离的志愿者人类 B 细胞和 T 细胞中的作用，这些细胞用脂多糖（LPS）和肽聚糖 G（PepG）孵育，作为体外脓毒症模型。

实验方法

使用 NOP 荧光探针 N/OFQ 测量 B 细胞和 T 细胞的 NOP 表达，使用免疫荧光法测量 N/OFQ 含量，使用 CHO 生物传感器测定法跟踪 N/OFQ 释放，使用 Transwell 迁移和细胞因子/趋化因子释放的 25 聚体测定法测量 NOP 功能。细胞受到 LPS/PepG 的刺激。

主要结果

CD19 阳性 B 细胞结合 N/OFQ；它们还含有 N/OFQ。CXCL13/IL-4 刺激增加了 N/OFQ 的释放。N/OFQ 趋势降低了对 CXCL13/IL-4 的迁移。LPS/PepG 对表面 NOP 表达没有影响，但这种处理以 N/OFQ 敏感的方式增加了 GM-CSF 的释放。CD3 阳性 T 细胞不结合 N/OFQ；它们确实含有 N/OFQ。CXCL12/IL-6 刺激增加了 N/OFQ 的释放。当与 LPS/PepG 孵育时，NOP 表面表达被诱导导致 N/OFQ 结合。在 LPS/PepG 处理的细胞中，N/OFQ 降低了对 CXCL12/IL-6 的迁移。LPS/PepG 以 N/OFQ 敏感的方式增加了 GM-CSF 的释放。

结论和意义

我们分别提出了脓毒症诱导的 B 细胞和 T 细胞功能的组成型和脓毒症诱导的孤啡肽-NOP 受体自分泌调节。这些 NOP 受体不同程度地抑制迁移并减少 GM-CSF 的释放。这些数据为增加的孤啡肽信号在脓毒症中的有害作用提供了机制见解，并表明 NOP 拮抗剂作为治疗方法的潜在作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a3/10953342/8c2a9a31d711/BPH-180-2298-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a3/10953342/e97ee1a34302/BPH-180-2298-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a3/10953342/0de43917fe0a/BPH-180-2298-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a3/10953342/c2b5e87132a9/BPH-180-2298-g006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1a3/10953342/8c2a9a31d711/BPH-180-2298-g008.jpg

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