Molecular Features and Stages of Pulmonary Fibrosis Driven by Type 2 Inflammation

Mattoo, Hamid; Bangari, Dinesh S.; Cummings, Sheila; Humulock, Zachary; Habiel, David M.; Pate, Nathan; Resnick, Robert H.; Savova, Virginia; Qian, George; Beil, Christian; Rao, Ercole; Nestle, Frank O.; Bryce, Paul J.; Subramaniam, Arun

doi:10.1165/rcmb.2022-0301oc

Cited by 4 publications

(2 citation statements)

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“…Circulating inflammatory cells, primarily monocytes and T lymphocytes, are recruited and, along with tissue-resident immune macrophages, they initiate the production of cytokines and chemokines, such as transforming growth factor-β1 (TGFβ1) and interleukine-10 (IL10) [ 3 ]. Recent studies have identified monocytes and macrophages as possible crucial mediators of the fibrotic process in SSc [ 4 – 7 ].…”

Section: Introductionmentioning

confidence: 99%

Nintedanib downregulates the profibrotic M2 phenotype in cultured monocyte-derived macrophages obtained from systemic sclerosis patients affected by interstitial lung disease

Soldano,

Smith,

Montagna

et al. 2024

Arthritis Res Ther

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Background Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by vasculopathy and progressive fibrosis of skin and several internal organs, including lungs. Macrophages are the main cells involved in the immune-inflammatory damage of skin and lungs, and alternatively activated (M2) macrophages seem to have a profibrotic role through the release of profibrotic cytokines (IL10) and growth factors (TGFβ1). Nintedanib is a tyrosine kinase inhibitor targeting several fibrotic mediators and it is approved for the treatment of SSc-related interstitial lung disease (ILD). The study aimed to evaluate the effect of nintedanib in downregulating the profibrotic M2 phenotype in cultured monocyte-derived macrophages (MDMs) obtained from SSc-ILD patients. Methods Fourteen SSc patients, fulfilling the 2013 ACR/EULAR criteria for SSc, 10 SSc patients affected by ILD (SSc-ILD pts), 4 SSc patients non affected by ILD (SSc pts no-ILD), and 5 voluntary healthy subjects (HSs), were recruited at the Division of Clinical Rheumatology-University of Genova, after obtaining Ethical Committee approval and patients’ informed consent. Monocytes were isolated from peripheral blood, differentiated into MDMs, and then maintained in growth medium without any treatment (untreated cells), or treated with nintedanib (0.1 and 1µM) for 3, 16, and 24 h. Gene expression of macrophage scavenger receptors (CD204, CD163), mannose receptor-1 (CD206), Mer tyrosine kinase (MerTK), identifying M2 macrophages, together with TGFβ1 and IL10, were evaluated by quantitative real-time polymerase chain reaction. Protein synthesis was investigated by Western blotting and the level of active TGFβ1 was evaluated by ELISA. Statistical analysis was carried out using non-parametric Wilcoxon test. Results Cultured untreated SSc-ILD MDMs showed a significant increased protein synthesis of CD206 (p < 0.05), CD204, and MerTK (p < 0.01), together with a significant upregulation of the gene expression of MerTK and TGFβ1 (p < 0.05; p < 0.01) compared to HS-MDMs. Moreover, the protein synthesis of CD206 and MerTK and the gene expression of TGFβ1 were significantly higher in cultured untreated MDMs from SSc-ILD pts compared to MDMs without ILD (p < 0.05; p < 0.01). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly downregulated the gene expression and protein synthesis of CD204, CD206, CD163 (p < 0.05), and MerTK (p < 0.01) compared to untreated cells after 24 h of treatment. Limited to MerTK and IL10, both nintedanib concentrations significantly downregulated their gene expression already after 16 h of treatment (p < 0.05). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly reduced the release of active TGFβ1 after 24 h of treatment (p < 0.05 vs. untreated cells). Conclusions In cultured MDMs from SSc-ILD pts, nintedanib seems to downregulate the profibrotic M2 phenotype through the significant reduction of gene expression and protein synthesis of M2 cell surface markers, together with the significant reduction of TGFβ1 release, and notably MerTK, a tyrosine kinase receptor involved in lung fibrosis.

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Section: Introductionmentioning

confidence: 99%

Nintedanib downregulates the profibrotic M2 phenotype in cultured monocyte-derived macrophages obtained from systemic sclerosis patients affected by interstitial lung disease

Soldano,

Smith,

Montagna

et al. 2024

Arthritis Res Ther

View full text Add to dashboard Cite

show abstract

“…In this issue of the Journal , Mattoo and colleagues (pp. 404–421 ) characterize the progressive molecular changes in the pathogenesis of scleroderma and demonstrate the therapeutic benefits of neutralizing Th2 signaling in Fra2-tg mice ( 11 ). The investigative team identified pathways that might be responsible for lung pathology in patients with SSc in whom interstitial lung disease develops by analyzing existing gene-expression datasets from SSc/interstitial lung disease lungs ( 12 , 13 ).…”

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confidence: 99%