Sarcoidosis is a systemic inflammatory disease with significant morbidity and increased mortality and affects patients of all ages and races [1]. This condition is characterized by the formation of granulomas in different organs, most often in the lungs leading to the development of lung fibrosis [2]. The etiology of sarcoidosis remains unclear, however, genetic susceptibility, infection such as Propionibacterium acnes (PA), aberrant immune response, and environmental factors are believed to contribute to the pathogenesis of sarcoidosis [3], [4], [5], [6].

Glucocorticoids, including dexamethasone, are commonly prescribed drugs against inflammatory and immune disorders, including sarcoidosis [7]. Accumulating evidence has revealed that dexamethasone is effective in regulating inflammation and immune responses in sarcoidosis and improves the life quality of sarcoidosis patients [8], [9]. The intravitreal dexamethasone implant is reported as a safe and effective method that improves the visual acuity and reduces intraocular inflammation in the treatment of ocular sarcoidosis [10]. Dexamethasone is also recommended for the treatment of neurosarcoidosis in China [11]. Additionally, dexamethasone is commonly used to treat immune-related diseases [12]. For example, dexamethasone suppresses the Th17/Th1 cells polarization in primary immune thrombocytopenia patients [13]. Dexamethasone as an immunosuppressive glucocorticoid can induce the generation of tolerogenic dendritic cells, which modulates CD4+ T cell response in the immunotherapy for rheumatoid arthritis [14]. However, the underlying mechanism of dexamethasone in the treatment of pulmonary sarcoidosis remains not fully explored, and it is still imperative to explore therapeutic targets for pulmonary sarcoidosis treatment.

CD4+ T cells play a crucial role in the development of immune-mediated granuloma [15]. Multiple T helper subsets can be developed, exhibiting diverse cytokine patterns and distinct effector functions [16], [17]. Sarcoidosis is marked by activated monocytes or macrophages and highly polarized T helper 1 (Th1) and Th17 cells consistent with continuous antigen stimulation, and the secretion of cytokines including TNF-α, IL-17A, and IL-23, etc. [18], [19]. Additionally, regulatory T cells (Tregs) is indicated to control immunopathology and maintain immune homeostasis in various immune-related diseases [18]. Several studies have demonstrated an imbalance in the Th17/Treg cell ratio, which plays a crucial role in the pathogenesis of inflammatory events and immune-mediated diseases, including sarcoidosis [15], [20], [21]. Thus, the regulation of Th17/Treg cells ratio is suggested as a potential therapeutic strategy for the treatment of pulmonary sarcoidosis. However, the precise mechanism by which dexamethasone regulates the balance between Th17 and Treg cells are still not fully understood.

TGF-β is a growth factor promoting the differentiation of CD4+ T cells to Th17 cells in the presence of IL-6, IL-17 or IL-21 [22]. The achievement of TGF-β function relies on the signal transduction and modulation of Smad proteins. A recent study has provided evidence suggesting that the TGF-β/Smad3 signaling is implicated in the regulation of Tregs function in sarcoidosis [23]. In addition, dexamethasone has been demonstrated to relieve bleomycin-caused lung fibrosis in vivo by regulating the TGF-β, Smad3 and JAK-STAT pathways [24]. However, the effects of dexamethasone on the TGF-β/Smad3 signaling in sarcoidosis are rarely investigated.

In this study, our objective was to explore the underlying mechanism by which dexamethasone treats pulmonary sarcoidosis. The Propionibacterium acnes (PA) induced pulmonary sarcoidosis mouse model was established, and dexamethasone treatment was indicated to alleviate pulmonary sarcoidosis in vivo by inducing Th17/Treg cells rebalance via regulating the TGF-β/Smad3 signaling pathway, which may shed new light on the pulmonary sarcoidosis treatment.