Abstract
Silicosis is caused by exposure to crystalline silica (CS). We have previously shown that blocking 4-1BB signaling attenuated CS-induced inflammation and pulmonary fibrosis. However, the cells that express 4-1BB, which plays a vital role in promoting fibrosis, are still unknown. In this study, we demonstrated that the expression of 4-1BB is elevated in alveolar macrophages (AMs) in the lungs of CS-injured mice. CS exposure also markedly enhanced the expression of 4-1BB in macrophage-like, MH-S cells. In these cells, activation of the 4-1BB signaling with an agonist antibody led to upregulated secretion of pro-fibrotic mediators. Consistently, blocking 4-1BB downstream signaling or genetic deletion of 4-1BB alleviated pro-fibrotic responses in vitro, while treatment with a 4-1BB fusion protein promoted pro-fibrotic responses. In vivo experiments showed that blocking 4-1BB signaling decreased the expressions of pro-fibrotic mediators and fibrosis. These data suggest that 4-1BB signaling plays an important role in promoting AMs-mediated pro-fibrotic responses and pulmonary fibrosis. Our findings may provide a potential molecular target to reduce CS-induced fibrotic responses in occupational lung disease.
Highlights
Silicosis is a progressive, occupational lung disease, caused by long-term inhalation of crystalline silica (CS) [1]
We showed that 4-1BB levels increase on the surface of alveolar macrophages (AMs) in a mouse model of experimental silicosis
We verified that 4-1BB signaling in macrophage-like cells affected the secretion of pro-inflammatory and pro-fibrotic cytokines, chemokines, and matrix metalloproteinases (MMPs) after exposure to CS
Summary
Occupational lung disease, caused by long-term inhalation of crystalline silica (CS) [1]. 4-1BB Signaling Promotes Pro-Fibrotic Responses engulf CS are the first line of defense in immunity and exhibit a vital regulatory role at all stages of silicosis [8]. They can secrete pro-inflammatory and pro-fibrotic cytokines, chemokines, and matrix metalloproteinases (MMPs) in response to CS [9]. CS stimulation could induce 4-1BB expression on macrophage-like MH-S cells Using these cells as a model of AMs, we show that 4-1BB signaling promoted the release of pro-inflammatory and pro-fibrotic cytokines, chemokines, and MMPs. Consistent with this, blockade of 4-1BB signaling alleviated pro-fibrotic responses in vitro. Our data identify an encouraging function of 4-1BB signaling in AMs-mediated pro-fibrotic responses and CS-induced pulmonary fibrosis
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