Background.: Obliterative bronchiolitis (OB) remains the major complication limiting long-term survival of patients after lung transplantation. We aimed to explore the effects of the selective NACHT, LRR, and PYD domains-containing protein 3 (Nlrp3) inflammasome inhibitor MCC950 on the pathogenesis of OB. Methods.: Mouse orthotopic tracheal transplants were performed to mimic OB. MCC950 (50 mg/kg) or saline was intraperitoneally injected daily. The luminal occlusion rate and collagen deposition were evaluated by hematoxylin and eosin and Masson’s trichrome staining, respectively. Infiltration of CD4+, CD8+ T cells, and neutrophils was detected with immunohistochemical staining. The frequencies of T helper 1 cell (Th1), T helper 17 cell (Th17), and regulatory T cells (Treg) were measured by flow cytometry. Cytokine levels were measured by ELISA kits. Results.: MCC950 treatment significantly inhibited Nlrp3 inflammasome activation after allogeneic tracheal transplant and markedly decreased the luminal occlusion rate and collagen deposition in the allograft. The numbers of infiltrating CD4+, CD8+ T cells, and neutrophils in the allograft were also significantly reduced by MCC950 treatment. MCC950 dramatically decreased the frequencies of Th1/Th17 cells and the levels of interferon gamma/interleukin (IL)-17A and increased the Treg cell frequencies and IL-10 level; however, these effects were abolished by the addition of IL-1β and IL-18 both in vitro and in vivo. OB was also rescued by the addition of IL-1β and/or IL-18. Conclusions.: Blocking Nlrp3 inflammasome activation with MCC950 ameliorates OB lesions. The mechanistic analysis showed that MCC950 regulated the balance of Th1/Th17 and Treg cells and that this process is partially mediated by inhibition of IL-1β and IL-18. Therefore, targeting the Nlrp3 inflammasome is a promising strategy for controlling OB after lung transplantation.

Immunotherapy can improve the survival of patients with advanced lung squamous cell carcinoma (LUSC). T cytotoxic cells are one of the main members of the immune microenvironment. Herein, we aimed to identify the roles of T-cell cytotoxic markers interleukin 18 (IL18) receptor 1 (IL18R1) in the LUSC progression using bioinformatics, clinical tissue specimen, and cell experiment. We assessed the association between the IL18R1 expression and immune infiltration and IL18R1-related competing RNA network. The IL18R1 expression was downregulated in the LUSC tissues. The IL18R1 expression downregulation was associated with diagnosis and short overall survival and disease-specific survival, and it was also an independent risk factor for dismal survival time in LUSC. IL18R1-related nomograms predicted the survival time of patients with LUSC. IL18R1 overexpression inhibited the proliferation, migration, and invasion of LUSC cells. The IL18R1 expression was significantly associated with the microenvironment (stromal, immune, and estimate scores), immune cells (such as the T cells, cytotoxic cells, CD8 T cells), and immune cell markers (such as the CD8A, PD-1, and CTLA4) in LUSC. AC091563.1 and RBPMS-AS1 downregulation was positively associated with the IL18R1 expression, negatively associated with the miR-128-3p expression, and associated with short disease-specific survival and progression in LUSC. In conclusion, IL18R1 was significantly downregulated and associated with the prognosis and immune microenvironment. IL18R1 overexpression inhibits the growth and migration of cancer cells in LUSC. Furthermore, AC091563.1 and RBPMS-AS1 might compete with IL18R1 to bind miR-128-3p for participating in LUSC progression. These results showed that IL18R1 is a biomarker for evaluating the prognosis of patients with LUSC.

The roles and mechanisms of T-cell receptor (TCR)-associated transmembrane adaptor 1 (TRAT1) in lung adenocarcinoma (LAC) have not yet been reported in the relevant literature. Therefore, this study aimed to understand the roles and mechanisms of TRAT1 in LAC using bioinformatics and in vitro experiments. TRAT1 expression levels in LAC samples were analysed using various databases. TRAT1 co-expressed genes were acquired by the correlation analysis of LAC tissues. The functional mechanisms and protein network of TRAT1 co-expressed genes were analysed using bioinformatics analysis. The expression of TRAT1 was activated in LAC cells, and the roles of TRAT1 overexpression in the growth and migration of cancer cells was investigated using flow cytometry, Cell Counting Kit-8 (CCK-8), and migration and invasion assays. The relationship between TRAT1 overexpression, the immune microenvironment, and RNA modification was evaluated using correlation analysis. TRAT1 expression levels were significantly abnormal at multiple mutation sites and were related to the prognosis of LAC. TRAT1 co-expressed genes were involved in cell proliferation, adhesion, and differentiation, and TRAT1 overexpression significantly inhibited cell viability, migration, and invasion and promoted apoptosis of A549 and H1299 cells, which might be related to the TCR, B cell receptor (BCR), MAPK, and other pathways. TRAT1 expression levels were significantly correlated with the ESTIMATE, immune, and stromal scores in the LAC microenvironment. Additionally, TRAT1 expression levels were significantly correlated with the populations of B cells, CD8 T cells, cytotoxic cells, and other immune cells. TRAT1 overexpression was significantly correlated with the expression of immune cell markers (such as PDCD1, CD2, CD3E) and genes involved in RNA modification (such as ALKBH1, ALKBH3, ALKBH5). In conclusions, TRAT1 overexpression inhibited the growth and migration of LAC cells, thereby delaying cancer progression, and was correlated with the LAC microenvironment and RNA modifications.