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糖尿病合并结核病接触者的人肺泡巨噬细胞功能受损。

HUMAN ALVEOLAR MACROPHAGE FUNCTION IS IMPAIRED IN TUBERCULOSIS CONTACTS WITH DIABETES.

作者信息

Kleynhans Léanie, Kunsevi-Kilola Carine, Tshivhula Happy, Webber Tariq, Keyser Alana, Prins Nicole, Snyders Candice I, Shabangu Ayanda, Rozot Virginie, Kidd Martin, Zhang Hao, Cai Hong, Wang Yufeng, Ewing Adam D, Malherbe Stephanus T, Azad Abul K, Arnett Eusondia, Restrepo Blanca I, Schlesinger Larry S, Ronacher Katharina

机构信息

DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, SA MRC Centre for TB Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.

出版信息

Res Sq. 2024 Nov 28:rs.3.rs-5489046. doi: 10.21203/rs.3.rs-5489046/v1.

DOI:10.21203/rs.3.rs-5489046/v1
PMID:39649174
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11623777/
Abstract

Type 2 diabetes (T2D) increases susceptibility to tuberculosis (TB) with the underlying mechanisms remaining unknown. To determine whether immune dysfunction in the lung contributes to TB susceptibility, we obtained paired human alveolar macrophages (HAMs) and monocyte-derived macrophages (MDMs) from TB-exposed individuals with/without T2D. Upon infection with ( T2D-HAMs had more growth and produced more TNF. There were fewer neutrophils in the bronchoalveolar lavage of T2D patients which was inversely correlated with growth. Both T2D-HAMs and MDMs expressed less CD32, with T2D patients having fewer M1-like MDMs. T2D-MDMs produced less IL-1RA and CSF2. Overall -induced gene expression was delayed in T2D-HAMs, but genes involved in negative regulation of neutrophil migration were upregulated. T2D-HAM DNA was hypermethylated compared to control HAMs, however genes linked to TNF signalling were hypomethylated. We show here the first in-depth analysis of T2D-HAMs providing an explanation for more severe TB in T2D patients.

摘要

2型糖尿病（T2D）会增加患结核病（TB）的易感性，但其潜在机制尚不清楚。为了确定肺部的免疫功能障碍是否会导致结核病易感性，我们从有/无T2D的结核病暴露个体中获取了配对的人肺泡巨噬细胞（HAMs）和单核细胞衍生巨噬细胞（MDMs）。感染后，（T2D-HAMs有更多的生长并产生更多的TNF。T2D患者的支气管肺泡灌洗中中性粒细胞较少，这与生长呈负相关。T2D-HAMs和MDMs均表达较少的CD32，T2D患者的M1样MDMs较少。T2D-MDMs产生较少的IL-1RA和CSF2。总体而言，T2D-HAMs中诱导的基因表达延迟，但参与中性粒细胞迁移负调控的基因上调。与对照HAMs相比，T2D-HAM DNA发生了高甲基化，然而与TNF信号传导相关的基因发生了低甲基化。我们在此展示了对T2D-HAMs的首次深入分析，为T2D患者中更严重的结核病提供了解释。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f204/11623777/495b723c6a0d/nihpp-rs5489046v1-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f204/11623777/008131849855/nihpp-rs5489046v1-f0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f204/11623777/af280b585166/nihpp-rs5489046v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f204/11623777/c2a03a9b724f/nihpp-rs5489046v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f204/11623777/1677145c6b5f/nihpp-rs5489046v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f204/11623777/495b723c6a0d/nihpp-rs5489046v1-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f204/11623777/008131849855/nihpp-rs5489046v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f204/11623777/b9e2c707221e/nihpp-rs5489046v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f204/11623777/6b9aa6db4482/nihpp-rs5489046v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f204/11623777/21b5ff50b92a/nihpp-rs5489046v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f204/11623777/af280b585166/nihpp-rs5489046v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f204/11623777/c2a03a9b724f/nihpp-rs5489046v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f204/11623777/1677145c6b5f/nihpp-rs5489046v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f204/11623777/495b723c6a0d/nihpp-rs5489046v1-f0008.jpg

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本文引用的文献

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2
Human Macrophages Activate Bystander Neutrophils' Metabolism and Effector Functions When Challenged with .当受到挑战时，人类巨噬细胞会激活旁观者中性粒细胞的代谢和效应功能。
Int J Mol Sci. 2024 Mar 1;25(5):2898. doi: 10.3390/ijms25052898.
3
A new tractable method for generating human alveolar macrophage-like cells to study lung inflammatory processes and diseases.
一种新的可处理方法，用于生成人肺泡巨噬细胞样细胞，以研究肺部炎症过程和疾病。
mBio. 2023 Aug 31;14(4):e0083423. doi: 10.1128/mbio.00834-23. Epub 2023 Jun 8.
4
Human alveolar macrophage metabolism is compromised during infection.人类肺泡巨噬细胞在感染期间的代谢受到损害。
Front Immunol. 2023 Jan 26;13:1044592. doi: 10.3389/fimmu.2022.1044592. eCollection 2022.
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Tuberculosis alters immune-metabolic pathways resulting in perturbed IL-1 responses.结核病改变免疫代谢途径，导致 IL-1 反应失调。
Front Immunol. 2022 Dec 14;13:897193. doi: 10.3389/fimmu.2022.897193. eCollection 2022.
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Unique Reciprocal Association Seen Between Latent Tuberculosis Infection and Diabetes Is Due to Immunoendocrine Modulation (DM-LTB-1).潜伏性结核感染与糖尿病之间存在独特的相互关联，这是由于免疫内分泌调节所致（DM-LTB-1）。
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Human Macrophages Exhibit GM-CSF Dependent Restriction of Infection Regulating Their Self-Survival, Differentiation and Metabolism.人类巨噬细胞表现出 GM-CSF 依赖性限制感染，调节其自我存活、分化和代谢。
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A Blunted GPR183/Oxysterol Axis During Dysglycemia Results in Delayed Recruitment of Macrophages to the Lung During Mycobacterium tuberculosis Infection.在糖代谢紊乱期间，GPR183/氧化固醇轴被钝化，导致分枝杆菌感染时肺部巨噬细胞的募集延迟。
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Mucosal Immunol. 2022 Feb;15(2):223-234. doi: 10.1038/s41385-021-00480-w. Epub 2022 Jan 11.
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