No abstract

Background: DNA sensors are innate immune receptors that detect intracellular endogenous or exogenous DNA. They are critical to trigger immune response against DNA viral and intracellular bacterial infection, and are involved in inflammatory diseases and tumorigenesis. Recent accumulating evidences indicated that DNA sensors are also crucial for controlling the development of colorectal cancer (CRC). However, a systematic study on the expression profile of DNA sensors in CRC and their clinical significance are still lacking. Methods: We investigated the expression profile of DNA sensors in CRC and their clinical significance by taking advantage of clinical CRC samples, mouse AOM/DSS treatment model, and Oncomine ® bioinformatics platform. Results: Our study identified that the expression of DNA sensors, including AIM2, DAI, as well as inflammasome molecules ASC/IL-18, TLR9 and adaptor MyD88, and DDX60 decreased in human CRC, whereas the expression of DHX9, DHX36, and DDX41 significantly increased. Among them, the expression of AIM2/ASC/IL-18, MyD88, DAI, DHX36, and DDX60 were associated with cancer stages. In addition, we also performed correlation analysis between DNA sensors and their main signaling molecules to explore the possible mechanisms. The results showed that there were positive correlations between AIM2 and ASC/IL-18, DHX9 and MAVS, and TLR9 and MyD88 expression. In addition, the gene expression patterns of some DNA sensors were confirmed by Western-blot analysis. Conclusions: Our study revealed that the expression of multiple DNA sensors was deregulated in CRC and might be involved in tumor development. More importantly, the study identified that, among all these DNA sensors, AIM2, DAI, and DDX60 could be potentially critical for diagnosis, prognosis, and therapy of CRC and deserve further investigation.

Exposure to diesel exhaust particles (DEPs) is associated with acute inflammatory responses in the lung and exacerbation of respiratory diseases. However, the mechanism by which DEPs trigger the inflammatory responses remains unclear. Here, we demonstrated that the IFN response factors IRF3 and IRF7 played pivotal roles in DEP‐induced pulmonary inflammation. DEPs could not directly induce inflammatory cytokine expression in mouse cells, whereas DEPs triggered autophagy both in vitro and in vivo. The DEP‐induced autophagy was augmented in the absence of IRF3 and IRF7, but not in the absence of IFNAR. The expression of Raptor was induced by IRF3 and IRF7 in response to DEPs treatment. Furthermore, administration of the mechanistic target of rapamycin (mTOR) inhibitor alleviated the inflammatory responses in the lung during DEP exposure. Our findings define an IFNAR‐independent role of increased autophagy in the absence of IRF3 and IRF7 during pulmonary DEP exposure, and provide the basis to develop new therapeutic approaches to counteract the adverse effects of DEPs and possibly other ambient particulate matters.

Background RNA sensors represent the most important pattern recognition receptors (PRRs) to defend against RNA pathogens, such as RNA viruses. Recent studies revealed their critical roles in inflammatory and autoimmune diseases. Furthermore, more recent evidences indicated that RNA sensors mediate the development of colitis or colorectal cancer (CRC). However, a systematic understanding of RNA sensors in CRC is still lacking, especially the expression patterns in CRC. Methods Here, we analyzed RNA sensor expression, clinical significance, and possible mechanisms in CRC by combining bioinformatic analysis and the analysis on pre-cancerous animal model and clinical tissue samples. Results We found that most of the members of RNA sensors, including RNA-sensing Toll-like receptors ( TLR3 , TLR7 , and TLR8 ) and RIG-I-like receptors ( MDA5 and RIG-I ), were down-regulated in CRC, while the expression of DDX21 were up-regulated in human CRC. In addition, we also analyzed the correlation between gene expression and cancer stages. We found that the expression of RNA-sensing TLRs, RIG-I , and DDX21 in CRC were associated with cancer stages. Finally, in order to explore the possible mechanisms, the correlation between RNA sensors and the main downstream signaling molecules were analyzed. A positive correlation was observed in TLR7/8 and MyD88 , RIG-I/MDA5 and LGP2 , while a negative correlation was observed in RIG-I/MDA5 and MAVS . Conclusions This study reveals the potential values of RNA-sensing genes including TLRs, RIG-I and DDX21 as biomarkers of CRC formation, progression and therapy.