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Iron deposition and chronic inflammation are associated with chronic liver diseases, such as alcoholic liver disease, nonalcoholic fatty liver disease, and chronic hepatitis B and C. However, the relationship between iron deposition and chronic inflammation in these diseases is still unclear. In the current study, we aimed to investigate the effect of iron on chronic inflammation in HepG2 cells and mice liver. We demonstrated that iron treatment enhanced the expression of cGAS, STING, and their downstream targets, including TBK1, IRF-3, and NF-κB in HepG2 cells and mice liver. We also found that treatment of HepG2 cells and mice with ferric ammonium citrate increased the expression of inflammatory cytokines, such as IFN-β. Finally, we found that genes involved in iron metabolism and the STING signaling pathway were up-regulated in liver cancer tissues, and the survival time of patients with high expression of these genes in tumor tissues was significantly shortened. These results suggest that iron overload may promote the progress of the chronic liver disease by activating cGAS-STING-mediated chronic inflammation, which provides a new idea for the development of drugs for the treatment of the chronic liver disease.

ZD55-IL-24 is similar but superior to the oncolytic adenovirus ONYX-015, yet the exact mechanism underlying the observed therapeutic effect is still not well understood. Here we sought to elucidate the underlying antitumor mechanism of ZD55-IL-24 in both immunocompetent and immunocompromised mouse model. We find that ZD55-IL-24 eradicates established melanoma in B16-bearing immunocompetent mouse model not through the classic direct killing pathway, but mainly through the indirect pathway of inducing systemic antitumor immunity. Inconsistent with the current prevailing view, our further results suggest that ZD55-IL-24 can induce antitumor immunity in B16-bearing immunocompetent mouse model in fact not due to its ability to lyse tumor cells and release the essential elements, such as tumor-associated antigens (TAAs), but due to its ability to put a “nonself” label in tumor cells and then turn the tumor cells from the “self” state into the “nonself” state without tumor cell death. The observed anti-melanoma efficacy of ZD55-IL-24 in B16-bearing immunocompetent mouse model was practically caused only by the viral vector. In addition, we also notice that ZD55-IL-24 can inhibit tumor growth in B16-bearing immunocompetent mouse model through inhibiting angiogenesis, despite it plays only a minor role. In contrast to B16-bearing immunocompetent mouse model, ZD55-IL-24 eliminates established melanoma in A375-bearing immunocompromised mouse model mainly through the classic direct killing pathway, but not through the antitumor immunity pathway and anti-angiogenesis pathway. These findings let us know ZD55-IL-24 more comprehensive and profound, and provide a sounder theoretical foundation for its future modification and drug development.

Although the recent treatment in melanoma through the use of anti-PD-1 immunotherapy is successful, the efficacy of this approach remains to be improved. Here, we explore the feasibility of combination strategy with the armed oncolytic adenovirus ZD55-IL-24 and PD-1 blockade. We find that combination therapy with localized ZD55-IL-24 and systemic PD-1 blockade leads to synergistic inhibition of both local and distant established tumors in B16-bearing immunocompetent mouse model. Our further mechanism investigation reveals that synergistic therapeutic effect is associated with marked promotion of tumor immune infiltration and recognition in both local and distant tumors as well as spleens. PD-1 blockade has no obvious effect on promotion of tumor immune infiltration and recognition. Localized therapy with ZD55-IL-24, however, can help PD-1 blockade to overcome the limitation of relatively low tumor immune infiltration and recognition. This study provides a rationale for investigation of such combination therapy in the clinic.

BackgroundEnvironmental etiology of primary Sjögren’s syndrome (pSS), an autoimmune disease, has been proposed. This study determined whether the exposure to air pollutants was an independent risk factor for pSS.MethodsParticipants were enrolled from a population-based cohort registry. Daily average concentrations of air pollutants from 2000 to 2011 were divided into 4 quartiles. Adjusted hazard ratios (aHRs) of pSS for exposure to air pollutants were estimated in a Cox proportional regression model adjusting for age, sex, socioeconomic status, and residential areas. A subgroup analysis stratified by sex was conducted to validate the findings. Windows of susceptibility indicated years of exposure which contributed the most to the observed association. Ingenuity Pathway Analysis was used to identify underlying pathways of air pollutant-associated pSS pathogenesis, using Z-score visualization.ResultsTwo hundred patients among 177,307 participants developed pSS, with a mean age of 53.1 years at acumulative incidence of 0.11% from 2000 to 2011. Exposure to carbon monoxide (CO), nitric oxide (NO), and methane (CH4) was associated with a higher risk of pSS. Compared to those exposed to the lowest concentration level, the aHRs for pSS were 2.04 (95%CI=1.29-3.25), 1.86 (95%CI=1.22-2.85), and 2.21 (95%CI=1.47-3.31) for those exposed to high levels of CO, NO, and CH4, respectively. The findings persisted in the subgroup analysis, in which females exposed to high levels of CO, NO, and CH4 and males exposed to high levels of CO were associated with significantly great risk of pSS. The cumulative effect of air pollution on pSS was time-dependent. The underlying cellular mechanisms involved chronic inflammatory pathways including the interleukin-6 signaling pathway.ConclusionExposure to CO, NO, and CH4 was associated with a high risk of pSS, which was biologically plausible.