Division of Allergy and Immunology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States of America.
Veterans Affairs Nebraska-Western Iowa Health Care System, Research Service, Omaha, NE, United States of America.
PLoS One. 2021 Feb 12;16(2):e0240707. doi: 10.1371/journal.pone.0240707. eCollection 2021.
Rheumatoid arthritis (RA)-associated lung disease is a leading cause of mortality in RA, yet the mechanisms linking lung disease and RA remain unknown. Using an established murine model of RA-associated lung disease combining collagen-induced arthritis (CIA) with organic dust extract (ODE)-induced airway inflammation, differences among lung immune cell populations were analyzed by single cell RNA-sequencing. Additionally, four lung myeloid-derived immune cell populations including macrophages, monocytes/macrophages, monocytes, and neutrophils were isolated by fluorescence cell sorting and gene expression was determined by NanoString analysis. Unsupervised clustering revealed 14 discrete clusters among Sham, CIA, ODE, and CIA+ODE treatment groups: 3 neutrophils (inflammatory, resident/transitional, autoreactive/suppressor), 5 macrophages (airspace, differentiating/recruited, recruited, resident/interstitial, and proliferative airspace), 2 T-cells (differentiating and effector), and a single cluster each of inflammatory monocytes, dendritic cells, B-cells and natural killer cells. Inflammatory monocytes, autoreactive/suppressor neutrophils, and recruited/differentiating macrophages were predominant with arthritis induction (CIA and CIA+ODE). By specific lung cell isolation, several interferon-related and autoimmune genes were disproportionately expressed among CIA and CIA+ODE (e.g. Oasl1, Oas2, Ifit3, Gbp2, Ifi44, and Zbp1), corresponding to RA and RA-associated lung disease. Monocytic myeloid-derived suppressor cells were reduced, while complement genes (e.g. C1s1 and Cfb) were uniquely increased in CIA+ODE mice across cell populations. Recruited and inflammatory macrophages/monocytes and neutrophils expressing interferon-, autoimmune-, and complement-related genes might contribute towards pro-fibrotic inflammatory lung responses following airborne biohazard exposures in setting of autoimmune arthritis and could be predictive and/or targeted to reduce disease burden.
类风湿关节炎（RA）相关肺部疾病是导致 RA 患者死亡的主要原因，但肺部疾病与 RA 之间的关联机制尚不清楚。本研究采用胶原诱导关节炎（CIA）联合有机粉尘提取物（ODE）诱导气道炎症的 RA 相关肺部疾病小鼠模型，通过单细胞 RNA 测序分析肺部免疫细胞群体的差异。此外，通过荧光细胞分选分离了 4 种肺髓样来源的免疫细胞群体，包括巨噬细胞、单核细胞/巨噬细胞、单核细胞和中性粒细胞，并通过 NanoString 分析确定了基因表达。非监督聚类分析显示，在 Sham、CIA、ODE 和 CIA+ODE 治疗组中存在 14 个离散的聚类：3 种中性粒细胞（炎症性、常驻/过渡性、自身反应性/抑制性）、5 种巨噬细胞（气腔、分化/募集、募集、常驻/间质和增殖性气腔）、2 种 T 细胞（分化和效应），以及单个炎症性单核细胞、树突状细胞、B 细胞和自然杀伤细胞簇。关节炎诱导（CIA 和 CIA+ODE）时，炎症性单核细胞、自身反应性/抑制性中性粒细胞和募集/分化的巨噬细胞占优势。通过特定的肺细胞分离，CIA 和 CIA+ODE 中几种干扰素相关和自身免疫基因表达失调（如 Oasl1、Oas2、Ifit3、Gbp2、Ifi44 和 Zbp1），与 RA 和 RA 相关肺部疾病相对应。单核细胞髓样来源的抑制细胞减少，而补体基因（如 C1s1 和 Cfb）在 CIA+ODE 小鼠的所有细胞群体中均增加。表达干扰素、自身免疫和补体相关基因的募集和炎症性巨噬细胞/单核细胞和中性粒细胞可能导致自身免疫性关节炎患者暴露于空气传播生物危害后发生促纤维化炎症性肺部反应，并可作为预测和/或靶向治疗以减轻疾病负担。
