TNF-Induced Interstitial Lung Disease in a Murine Arthritis Model: Accumulation of Activated Monocytes, Conventional Dendritic Cells, and CD21

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 pathology. In both articular and pulmonary manifestations, tumor necrosis factor (TNF) is a significant pathogenic factor. While anti-TNF therapy ameliorates joint pathology, it exacerbates fibrotic RA-ILD. The TNF-transgenic (TNF-Tg) murine model of RA develops both inflammatory arthritis and an ILD which mimics a cellular non-specific interstitial pneumonia (NSIP) 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: 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 WT controls. Flow cytometry of TNF-Tg vs. WT lungs revealed significant increases in activated monocytes, conventional dendritic cells (cDC2), and CD21(+)/CD23(−) B cells that are phenotypically distinct from the Bin cells which are known to accumulate in joint draining lymph nodes. In contrast to human RA-ILD, anti-TNF treatment significantly ameliorated both joint and lung inflammation. These results identify a potential role for activated monocytes, cDC2, and CD21(+)/CD23(−) B cells in the genesis of RA-ILD, which exist in a previously unknown, reversible, pre-fibrotic stage of the disease.