Tofacitinib facilitates the expansion of myeloid-derived suppressor cells and ameliorates interstitial lung disease in SKG mice

Sendo, Sho; Saegusa, Jun; Yamada, Hiroyuki; Nishimura, Keisuke; Morinobu, Akio

doi:10.1186/s13075-019-1963-2

Cited by 55 publications

(52 citation statements)

References 22 publications

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“…Using a classical gating strategy (Ly6G -CD11b + Ly6C high SSC low ) for mMDSCs (99), mMDSCs were identified with FACS and found to be decreased in combination (CIA+ODE) exposure group. These findings are consistent with a recent report that showed that the expansion of MDSCs following tofacitinib treatment is inversely related to the progression of ILD in the SKG mouse model of RA-ILD (116). These collective findings would suggest a potential protective role for lung MDSCs (particularly mMDSCs) in the development RA-related lung disease, and future studies are warranted to understand their role in disease manifestations to potentially develop novel targets for therapeutic interventions.…”

Section: Discussionsupporting

confidence: 91%

High-Throughput Analysis of Lung Immune Cells in a Murine Model of Rheumatoid Arthritis-Associated Lung Disease

Gaurav

Mikuls

Thiele

et al. 2020

Preprint

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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.

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Section: Discussionsupporting

confidence: 91%

High-Throughput Analysis of Lung Immune Cells in a Murine Model of Rheumatoid Arthritis-Associated Lung Disease

Gaurav

Mikuls

Thiele

et al. 2020

Preprint

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“…Recently, tofacitinib demonstrated its ability to facilitate the expansion of myeloid-derived suppressor cells (MDSC) and ameliorate arthritis in SKG mice, a murine model developing not only arthritis but also ILD. In SKG mice, tofacitinib significantly suppressed the progression of ILD compared to control, by increasing myeloid-derived suppressor cells and suppressing Th17 cells proliferation and differentiation [180]. On the contrary, in another in vitro study, the JAK2 inhibition, but not the selective JAK1/JAK3 pathway, significantly reduced IL-17A-induced fibrogenic response in RA-ILD patients [181].…”

Section: Targeted Synthetic Disease-modifying Antirheumatic Drugs (Tsmentioning

confidence: 94%

Treatment of Rheumatoid Arthritis-Associated Interstitial Lung Disease: Lights and Shadows

Cassone

Manfredi

Vacchi

et al. 2020

JCM

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Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disease affecting 0.5–1% of the population worldwide. Interstitial lung disease (ILD) is a serious pulmonary complication of RA and it is responsible for 10–20% of mortality, with a mean survival of 5–8 years. However, nowadays there are no therapeutic recommendations for the treatment of RA-ILD. Therapeutic options for RA-ILD are complicated by the possible pulmonary toxicity of many disease modifying anti-rheumatic drugs (DMARDs) and by their unclear efficacy on pulmonary disease. Therefore, joint and lung involvement should be evaluated independently of each other for treatment purposes. On the other hand, some similarities between RA-ILD and idiopathic pulmonary fibrosis and the results of the recent INBIULD trial suggest a possible future role for antifibrotic agents. From this perspective, we review the current literature describing the pulmonary effects of drugs (immunosuppressants, conventional, biological and target synthetic DMARDs and antifibrotic agents) in patients with RA and ILD. In addition, we suggest a framework for the management of RA-ILD patients and outline a research agenda to fill the gaps in knowledge about this challenging patient cohort.

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“…Injection of zymosan into SKG mice can induce RA-ILD (Redente et al, 2018;Sendo et al, 2019). SKG female mice were injected with zymosan to construct RA-ILD mouse models.…”

Section: High Expression Of Hdac3 and Il17ra In Lung Tissues Of Ra-ilmentioning

confidence: 99%

Histone Deacetylase 3-Mediated Inhibition of microRNA-19a-3p Facilitates the Development of Rheumatoid Arthritis-Associated Interstitial Lung Disease

Li²,

et al. 2020

Front. Physiol.

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Histone deacetylase (HDAC) has been implicated in rheumatoid arthritis (RA) progression. We investigated the roles of histone deacetylase 3 (HDAC3) involved in RA-associated interstitial lung disease (ILD) fibrosis. Firstly, we measured the expression of HDAC3 and interleukin 17 receptor A (IL17RA) in lung tissue samples from normal controls, idiopathic pulmonary fibrosis (IPF) patients, and RA-ILD patients. Next, chromatin immunoprecipitation (ChIP) and dual luciferase reporter assay were employed to detect the interaction between HDAC3 and microRNA-19a-3p (miR-19a-3p) and between miR-19a-3p and IL17RA. Further, immunohistochemistry was used to localize HDAC3 and IL17RA expression in lung tissues. Additionally, functional assays were conducted followed by expression determination of HDAC3, miR-19a-3p, and IL17RA with reverse transcription quantitative PCR (RT-qPCR) and Western blot analysis. The effect of HDAC3 on RA-ILD in the constructed RA-ILD mouse model was also studied based on arthritis assessment. We found overexpressed HDAC3 and IL17RA as well as silenced miR-19a-3p in RA-ILD mouse model and RA-ILD patients. In the mouse model, HDAC3 downregulated miR-19a-3p in lung fibroblasts to promote the progression of RA-ILD fibrosis. In lung fibroblasts of RA-ILD mice, IL17RA was a target gene of miR-19a-3p. miR-19a-3p negatively regulated IL17RA, thereby increasing the expression of fibrosis markers, COL1A1, COL3A1, and FN, in lung fibroblasts of mice. Taken together, HDAC3 upregulated IL17RA expression by targeting miR-19a-3p to facilitate the RA-ILD fibrosis development, which sheds light on a new HDAC3/miR-19a-3p/IL17RA axis functioning in RA-ILD fibrosis.

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Tofacitinib facilitates the expansion of myeloid-derived suppressor cells and ameliorates interstitial lung disease in SKG mice

Cited by 55 publications

References 22 publications

High-Throughput Analysis of Lung Immune Cells in a Murine Model of Rheumatoid Arthritis-Associated Lung Disease

High-Throughput Analysis of Lung Immune Cells in a Murine Model of Rheumatoid Arthritis-Associated Lung Disease

Treatment of Rheumatoid Arthritis-Associated Interstitial Lung Disease: Lights and Shadows

Histone Deacetylase 3-Mediated Inhibition of microRNA-19a-3p Facilitates the Development of Rheumatoid Arthritis-Associated Interstitial Lung Disease

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