Blocking the 4-1BB Pathway Ameliorates Crystalline Silica-induced Lung Inflammation and Fibrosis in Mice

Abstract

Long term pulmonary exposure to crystalline silica leads to silicosis that manifests progressive interstitial fibrosis, eventually leading to respiratory failure and death. Despite efforts to eliminate silicosis, clinical cases continue to occur in both developing and developed countries. The exact mechanisms of crystalline silica-induced pulmonary fibrosis remain elusive. Herein, we find that 4-1BB is induced in response to crystalline silica injury in lungs and that it is highly expressed during development of experimental silicosis. Therefore, we explore the role of 4-1BB pathway during crystalline silica-induced lung injury and find that a specific inhibitor blocking the pathway could effectively alleviate crystalline silica-induced lung inflammation and subsequent pulmonary fibrosis in vivo. Compared to controls, the treated mice exhibited reduced Th1 and Th17 responses. The concentrations of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF), including tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-17A following crystalline silica challenge were also reduced in inhibitor-treated mice. Although there was no significant alteration in Th2 cytokines of IL-4 and IL-13, another type of pro-fibrogenic cell, regulatory T cell (Treg) was significantly affected. In addition, one of the major participants in fibrogenesis, fibrocyte recruited less due to the blockade. Furthermore, we demonstrated the decreased fibrocyte recruitment was associated with chemokine reductions in lung. Our study discovers the 4-1BB pathway signaling enhances inflammatory response and promotes pulmonary fibrosis induced by crystalline silica. The findings here provide novel insights into the molecular events that control crystalline silica-induced lung inflammation and fibrosis through regulating Th responses and the recruitment of fibrocytes in crystalline silica-exposed lung.

Trehalose Alleviates Crystalline Silica-Induced Pulmonary Fibrosis via Activation of the TFEB-Mediated Autophagy-Lysosomal System in Alveolar Macrophages

“…Silicosis is caused by the inhalation of respirable crystalline silica (CS), which causes persistent inflammation and irreversible fibrosis. Silicosis is a progressive condition that is almost always fatal even when exposure to CS dust has ceased [1][2][3]. It is generally accepted that alveolar macrophages (AMs) are the first and main target cells to contact with CS particles [4].…”

4-1BB Signaling Promotes Alveolar Macrophages-Mediated Pro-Fibrotic Responses and Crystalline Silica-Induced Pulmonary Fibrosis in Mice

“…An agonist-4-1BB mAb seems to aggravate the development of inflammatory metabolic diseases and infectious diseases ( 13 , 16 ). As our previous study demonstrated, blockade of 4-1BB signaling may decrease CS-induced inflammation and pulmonary fibrosis in vivo ( 17 ). Nevertheless, the role (including any regulatory mechanisms) and the profile of expression of 4-1BB in CS-induced pulmonary fibrosis are still unknown.…”

Immune Alteration Caused by Fibrous and Particulate Environmental Substances

“…Back to Th17, Li et al studied alteration of expression in 4-1BB (CD137, TNFRSF9) which is an inducible costimulatory receptor expressed on activated T cells, during lung injury caused by silica using animal model [67]. Then, inhibitor for 4-1BB revealed reduction of Th1 and Th17 responses measured by TNF-α, IFNγ, and I-17A production.…”