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肥胖个体中透明质酸的小片段增加，并通过 TLR 介导的固有免疫细胞激活导致低度炎症。

Small fragments of hyaluronan are increased in individuals with obesity and contribute to low-grade inflammation through TLR-mediated activation of innate immune cells.

机构信息

Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, Barcelona, Spain.

CIBERehd, Madrid, Spain.

出版信息

Int J Obes (Lond). 2022 Nov;46(11):1960-1969. doi: 10.1038/s41366-022-01187-z. Epub 2022 Jul 27.

DOI:10.1038/s41366-022-01187-z
PMID:35896710
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9584819/
Abstract

BACKGROUND AND AIM

Extracellular matrix (ECM) components released during excessive fat mass expansion are considered potential endogenous danger/alarm signals contributing to innate immune system activation. The aim of the current study was to specifically measure plasma levels of low molecular weight (LMW) hyaluronan (HA) and to evaluate its role as pro-inflammatory damage-associated molecular pattern (DAMP) on leukocyte response in the context of human obesity.

SUBJECTS AND METHODS

Participants were selected according to their body mass index (BMI, kg/m) as non-obese (BMI < 29.9, n = 18) and obese (BMI > 29.9, n = 33). Plasma samples were size-dependent fractionated using ion-exchange chromatography to specifically obtain LMW HA fractions that were subsequently quantified by ELISA. Cell incubation experiments with synthetic HA molecules were performed on freshly Ficoll-isolated neutrophils (PMN) and peripheral blood monocytes (PBMC). Leukocyte and adipose tissue gene expression was assessed by real-time PCR and NF-κB activation by western blot. Plasma cytokine levels were measured by fluorescent bead-based (Luminex) immunoassay.

RESULTS

We observed a statistically significant increase in the circulating levels of HA fragments of LMW in individuals with obesity which were consistent with significant up-regulated expression of the LMW HA synthesizing enzyme hyaluronan synthase-1 (HAS-1) in obese adipose tissue. Gene expression assessment of HA receptors revealed up-regulated levels for TLR2 in both obese PMN and PBMC. Synthetic HA molecules of different sizes were tested on leukocytes from healthy donors. LMW HA fragments (15-40 kDa) and not those from intermediate molecular sizes (75-350 kDa) induced a significant up-regulation of the expression of major pro-inflammatory cytokines such as IL-1β, MCP-1 and IL-8 in PBMC. Importantly, LMW HA was able to induce the phosphorylation of IKK α/β complex supporting its pro-inflammatory role through NF-κB activation.

CONCLUSION

Circulating LMW HA molecules are elevated in obesity and may play an important role in triggering low-grade inflammation and the development of metabolic complications.

摘要

背景与目的

在脂肪质量过度扩张过程中释放的细胞外基质 (ECM) 成分被认为是潜在的内源性危险/警报信号，有助于固有免疫系统的激活。本研究的目的是专门测量低分子量 (LMW) 透明质酸 (HA) 的血浆水平，并评估其作为促炎损伤相关分子模式 (DAMP) 在人类肥胖中的白细胞反应中的作用。

受试者和方法

根据体重指数 (BMI，kg/m) 选择受试者，分为非肥胖者 (BMI<29.9，n=18) 和肥胖者 (BMI>29.9，n=33)。使用离子交换色谱对血浆样本进行基于大小的分级分离，以特异性获得 LMW HA 级分，随后通过 ELISA 进行定量。使用合成 HA 分子在新鲜分离的嗜中性粒细胞 (PMN) 和外周血单核细胞 (PBMC) 上进行细胞孵育实验。通过实时 PCR 评估白细胞和脂肪组织的基因表达，并通过 Western blot 评估 NF-κB 激活。通过荧光珠基 (Luminex) 免疫测定法测量血浆细胞因子水平。

结果

我们观察到肥胖个体中循环 LMW HA 片段水平呈统计学显著增加，这与肥胖脂肪组织中 LMW HA 合成酶透明质酸合酶-1 (HAS-1) 的显著上调表达一致。HA 受体的基因表达评估显示，肥胖 PMN 和 PBMC 中的 TLR2 水平上调。不同大小的合成 HA 分子在健康供体的白细胞上进行了测试。LMW HA 片段 (15-40 kDa) 而不是中间分子量 (75-350 kDa) 的片段诱导 PBMC 中主要促炎细胞因子如 IL-1β、MCP-1 和 IL-8 的表达显著上调。重要的是，LMW HA 能够诱导 IKK α/β 复合物的磷酸化，通过 NF-κB 激活支持其促炎作用。

结论

循环中的 LMW HA 分子在肥胖中升高，可能在触发低度炎症和代谢并发症的发展中发挥重要作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19f0/9584819/bb495815994f/41366_2022_1187_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19f0/9584819/fdc58b56516d/41366_2022_1187_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19f0/9584819/e5c273748efe/41366_2022_1187_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19f0/9584819/99efc2dbc733/41366_2022_1187_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19f0/9584819/bb495815994f/41366_2022_1187_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19f0/9584819/fdc58b56516d/41366_2022_1187_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19f0/9584819/1c3fa0b0e90c/41366_2022_1187_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19f0/9584819/e5c273748efe/41366_2022_1187_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19f0/9584819/99efc2dbc733/41366_2022_1187_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19f0/9584819/bb495815994f/41366_2022_1187_Fig5_HTML.jpg

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