TNF-Induced Interstitial Lung Disease in a Murine Arthritis Model: Accumulation of Activated Monocytes, Conventional Dendritic Cells, and CD21+/CD23− B Cell Follicles Is Prevented with Anti-TNF Therapy

Abstract

Interstitial lung disease (ILD) is a well-known extra-articular manifestation of rheumatoid arthritis (RA). RA-associated ILD (RA-ILD) exists on a wide spectrum, with variable levels of inflammatory and fibrotic activity, although all subtypes are regarded as irreversible pathologic conditions. In both articular and pulmonary manifestations, TNF is a significant pathogenic factor. Whereas anti-TNF therapy alleviates joint pathologic conditions, it exacerbates fibrotic RA-ILD. The TNF-transgenic (TNF-Tg) murine model of RA develops both inflammatory arthritis and an ILD that mimics a cellular nonspecific interstitial pneumonia pattern dominated by an interstitial accumulation of inflammatory cells with minimal-to-absent fibrosis. Given the model’s potential to elucidate the genesis of inflammatory RA-ILD, we aim to achieve the following: 1) characterize the cellular accumulations in TNF-Tg lungs, and 2) assess the reversibility of inflammatory ILD following anti-TNF therapy known to resolve TNF-Tg inflammatory arthritis. TNF-Tg mice with established disease were randomized to anti-TNF or placebo therapy and evaluated with imaging, histology, and flow cytometric analyses, together with wild-type controls. Flow cytometry of TNF-Tg versus wild-type lungs revealed significant increases in activated monocytes, conventional dendritic cells, and CD21+/CD23− B cells that are phenotypically distinct from the B cells in inflamed nodes, which are known to accumulate in joint-draining lymph nodes. In contrast to human RA-ILD, anti-TNF treatment significantly alleviated both joint and lung inflammation. These results identify a potential role for activated monocytes, conventional dendritic cells, and CD21+/CD23− B cells in the genesis of RA-ILD, which exist in a previously unknown, reversible, prefibrotic stage of the disease.

Tumor Necrosis Factor Induces Obliterative Pulmonary Vascular Disease in a Novel Model of Connective Tissue Disease–Associated Pulmonary Arterial Hypertension

“…Our experiments with anti‐TNF treatment demonstrated pathologic resolution and yielded additional important insights. In addition to validating previous studies which have shown that TNF inhibition can ameliorate ILD in these mice and PAH in different species , our finding that anti‐TNF treatment both halts the evolution of pulmonary vascular disease and prevents RV remodeling even when started at 3 months of age demonstrates that this model represents a dynamic and modifiable phenotype which can likely be used to show both prevention and treatment of pulmonary hypertension under different conditions. This dramatic improvement also suggests that anti‐TNF therapy may be valuable as a treatment in CTD‐PAH, especially given the high degree of overlap seen between gene expression in the lungs of TNF‐Tg mice and patients with CTD‐PAH.…”

The mechanism of triptolide in the treatment of connective tissue disease-related interstitial lung disease based on network pharmacology and molecular docking

“…Tumour necrosis factor receptors and their corresponding cytokine ligands are involved in many aspects of immune function [ 42 ]. Activation of the TNF signalling pathway has been found to induce interstitial lung disease [ 43 ]. Interleukin (IL)-17 signal pathway has demonstrated pro-inflammatory effects in chronic inflammation and autoimmune diseases and showed pathogenicity in pulmonary fibrosis are potential therapeutic targets for the treatment of fibroproliferative lung diseases [ 44 ].…”

The mechanism of triptolide in the treatment of connective tissue disease-related interstitial lung disease using network pharmacology and molecular docking

“…TNF signaling pathway plays an important role in a variety of connective tissue diseases. Tumor necrosis factor (TNF) receptors and their corresponding cytokine ligands are involved in many aspects of immune functional [33], activation of TNF signaling pathway has been found to induce interstitial lung disease [34]. Interleukin(IL)-17 signal pathway demonstrated pro-in ammatory effects in chronic in ammation and autoimmune diseases, and showed pathogenicity in pulmonary brosis, are potent therapeutic targets for the treatment of broproliferative lung diseases [35].…”