The therapeutic potential of PD-1/PD-L1 pathway on immune-related diseases: Based on the innate and adaptive immune components.

Currently, immunotherapy targeting programmed cell death 1 (PD-1) or programmed death ligand 1 (PD-L1) has revolutionized the treatment strategy of human cancer patients. Meanwhile, PD-1/PD-L1 pathway has also been implicated in the pathogenesis of many immune-related diseases, such as autoimmune diseases, chronic infection diseases and adverse pregnancy outcomes, by regulating components of the innate and adaptive immune systems. Given the power of the new therapy, a better understanding of the regulatory effects of PD-1/PD-L1 pathway on innate and adaptive immune responses in immune-related diseases will facilitate the discovery of novel biomarkers and therapeutic drug targets. Targeting this pathway may successfully halt or potentially even reverse these pathological processes. In this review, we discuss recent major advances in PD-1/PD-L1 axis regulating innate and adaptive immune components in immune-related diseases. We reveal that the impact of PD-1/PD-L1 axis on the immune system is complex and manifold and multi-strategies on the targeted PD-1/PD-L1 axis are taken in the treatment of immune-related diseases. Consequently, targeting PD-1/PD-L1 pathway, alone or in combination with other treatments, may represent a novel strategy for future therapeutic intervention on immune-related diseases.

Targeting STING-mediated pro-inflammatory and pro-fibrotic effects of alveolar macrophages and fibroblasts blunts silicosis caused by silica particles.

Silica is utilized extensively in industrial and commercial applications as a chemical raw material, increasing its exposure and hazardous potential to populations, with silicosis serving as an important representative. Silicosis is characterized by persistent lung inflammation and fibrosis, for which the underlying pathogenesis of silicosis is unclear. Studies have shown that the stimulating interferon gene (STING) participates in various inflammatory and fibrotic lesions. Therefore, we speculated that STING might also play a key role in silicosis. Here we found that silica particles drove the double-stranded DNA (dsDNA) release to activate the STING signal pathway, contributing to alveolar macrophages (AMs) polarization by secreting diverse cytokines. Then, multiple cytokines could generate a micro-environment to exacerbate inflammation and promote the activation of lung fibroblasts, hastening fibrosis. Intriguingly, STING was also crucial for the fibrotic effects induced by lung fibroblasts. Loss of STING could effectively inhibit silica particles-induced pro-inflammatory and pro-fibrotic effects by regulating macrophages polarization and lung fibroblasts activation to alleviate silicosis. Collectively, our results have revealed a novel pathogenesis of silica particles-caused silicosis mediated by the STING signal pathway, indicating that STING may be regarded as a promising therapeutic target in the treatment of silicosis.

Dioscin ameliorates silica-aggravated systemic lupus erythematosus via suppressing apoptosis and improving LC3-associated phagocytosis in MRL/lpr mice.

Inhalation of silica not only directly leads to silicosis locally, but also results in various types of autoimmune diseases systemically, most commonly systemic lupus erythematosus (SLE). Little is known about the etiopathogenesis of silica-aggravated SLE to date, however, abnormal apoptosis and impaired apoptotic clearance have been reported to be closely related to the occurrence of SLE. LC3-associated phagocytosis (LAP) is a non-canonical form of autophagy, which plays a crucial role in mediating the clearance of apoptotic cells. Here we showed that the excessive accumulation of apoptotic debris in MRL/lpr mice exposed to silica might be due to the increased cell apoptosis and defective LAP caused by silica, thus accelerating the occurrence and progression of silica-aggravated SLE. Dioscin is an active ingredient in the family of Dioscoreaceae and is reported to possess multiple pharmacological activities, including anti-inflammatory, anti-apoptotic and autophagy-promoting properties. However, its role in SLE aggravated by silica exposure has not been investigated. In our study, we confirmed that dioscin decreased the accumulation of apoptotic debris by suppressing the excessive cell apoptosis and improving the LAP of immune cells in lung and spleen, leading to subsequent dramatically ameliorated lupus-like symptoms in silica-exposed MRL/lpr mice.

Inhibition of Galectin-3 attenuates silica particles-induced silicosis via regulating the GSK-3ß/ß-catenin signal pathway-mediated epithelial-mesenchymal transition.

Silica is a very common and important chemical raw material with a wide range of uses. Long-term inhalation of silica particles could cause lung toxicity, of which the most important representative is silicosis. Silicosis is a serious and fatal occupational pulmonary disease, characterized by persistent pulmonary inflammation and fibrosis. Despite intensive research, the toxic mechanism of silicosis caused by silica particles is not completely clear, which deserves further research and exploration. Many studies have indicated that the epithelial cells partially participate in the formation, accumulation, and activation of fibroblasts through epithelial-mesenchymal transition (EMT), which is conducive to the occurrence of fibrosis. Galectin-3 (Gal-3), widely expressed in epithelial cells, was observed to induce EMT in fibrotic diseases and tumors by regulating the GSK-3ß and ß-catenin. Previous studies have demonstrated that silica particles is indeed involved in the silicosis process by inducing EMT. However, it remains to be further studied whether there is a certain relationship between silica particles and Gal-3 expression, and whether Gal-3 also mediates the development of the silica particles-induced silicosis by regulating GSK-3ß/ß-catenin signal pathway-mediated EMT. Our research results showed that silica particles could significantly induce Gal-3 expression to promote the development of EMT through activating the GSK-3ß/ß-catenin signal pathway in mice and in A549 cells, which then significantly exacerbated the pulmonary fibrosis caused by silica particles. And the inhibition of Gal-3 could effectively inhibit the occurrence of EMT, and then effectively alleviate silicosis caused by silica particles. These findings would help us to further clarify the toxicological mechanisms of silicosis caused by silica particles and provide a novel target for prevention and intervention of silicosis.