Background and Aims: Schistosomiasis japonica is a widespread human zoonotic disease, and in China, there are many patients with schistosomiasis suffering from liver fibrosis. Many studies have shown that natural killer (NK) cells could reduce the progression of hepatic fibrosis by directly killing hepatic stellate cells (HSCs). However, NK cells could not inhibit the progress of liver fibrosis induced by Schistosoma japonicum infection. We aimed to investigate the function of NK cells in schistosomiasis. Methods: BALB/c mice were infected with S. japonicum cercariae. The receptors and their proportions expressed on NK cells in the liver and spleen from infected mice were detected using flow cytometry. Levels of IFN-γ, perforin, and granzyme of NK cells, and collagen I, III, and α-SMA of hepatic tissue, were detected using quantitative real-time PCR. Changes in cytokine levels in sera were detected using a cytometric bead array. Liver fibrosis was evaluated using hematoxylin and eosin and Masson staining. NK function in the schistosomiasis model was analyzed. Results: From 2 to 4 weeks post-infection, NK cells were activated, with significantly increased levels of effector molecules (IFN-γ, perforin, and granzyme) that peaked at 4 weeks after infection. The proportion of NK cells increased in the liver and spleen from 6 to 10 weeks post-infection. However, the function of NK cells was inhibited from 6 to 10 weeks post-infection with significantly decreased levels of activated receptors (AR), inhibitory receptors (IR), and effector molecules. The levels of IFN-γ, IL-12, and IL-6 in mouse serum peaked at 6 weeks post-infection, and IL-10 and IL-21 levels peaked at 8 weeks post-infection. Hepatic fibrosis markers increased significantly at 6 weeks after infection. Conclusion: Our study suggested that NK cells were activated from 2 to 4 weeks post-infection and participated in inflammation in the mouse model. After the S. japonicum laid their eggs, NK cells became inhibited, with decreased levels of both activating and inhibitory NK cell receptors, as well as cytotoxic molecules. In addition, liver fibrosis formed. In mice infected with S. japonicum, the process of liver fibrosis might be alleviated by removing the functional inhibition of NK cells.

Background: The main symptoms of schistosomiasis are granuloma and fibrosis, caused bySchistosomaeggs. Numerous types of cells and cytokines are involved in the progression ofSchistosomainfection. As a class of innate immune cells, γδ T cells play critical roles in the early immune response. However, their role in modulating granuloma and fibrosis remains to be clarified.Methods: Liver fibrosis in wild-type (WT) mice and T cell receptor (TCR) δ knockout (KO) mice infected withSchistosoma japonicumwas examinedviaMasson’s trichrome staining of collagen deposition and quantitative reverse transcriptase-PCR (RT-PCR) of fibrosis-related genes. Granuloma was detected by hematoxylin-eosin (H&E) staining and quantified. Flow cytometry was used for immune cell profiling and for detecting cytokine secretion. The abundance of the related cytokines was measured using quantitative RT-PCR.Results: The livers ofS. japonicum-infected mice had significantly increased proportions of interleukin (IL)-17A producing γδ T cells and secreted IL-17A. Compared with the WT mice, TCR δ deficiency resulted in reduced pathological impairment and fibrosis in the liver and increased survival in infected mice. In addition, the profibrogenic effects of γδ T cells in infected mice were associated with enhanced CD11b⁺Gr-1⁺cells, concurrent with increased expression of transforming growth factor (TGF)-β in the liver.Conclusions: In this mouse model ofSchistosomainfection, γδ T cells may promote liver fibrosis by recruiting CD11b⁺Gr-1⁺cells. These findings shed new light on the pathogenesis of liver pathology in murine schistosomiasis.

Schistosomiasis, which is caused by infection with Schistosoma spp., is characterized by granuloma and fibrosis in response to egg deposition. Pattern recognition receptors are important to sense invading Schistosoma, triggering an innate immune response, and subsequently shaping adaptive immunity. Cyclic GMP-AMP synthase (cGAS) was identified as a major cytosolic DNA sensor, which catalyzes the formation of cyclic GMP-AMP (cGAMP), a critical second messenger for the activation of the adaptor protein stimulator of interferon genes (STING). The engagement of STING by cGAMP leads to the activation of TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), and the subsequent type I interferon (IFN) response. cGAS is suggested to regulate infectious diseases, autoimmune diseases, and cancer. However, the function of cGAS in helminth infection is unclear. In this study, we found that Cgas deficiency enhanced the survival of mice infected with S. japonicum markedly, without affecting the egg load in the liver. Consistently, Cgas deletion alleviated liver pathological impairment, reduced egg granuloma formation, and decreased fibrosis severity. In contrast, Sting deletion reduced the formation of egg granulomas markedly, but not liver fibrosis. Notably, Cgas or Sting deficiency reduced the production of IFNβ drastically in mice infected with S. japonicum. Intriguingly, intravenous administration of recombinant IFNβ exacerbated liver damage and promoted egg granuloma formation, without affecting liver fibrosis. Clodronate liposome-mediated depletion of macrophages indicated that macrophages are the major type of cells contributing to the induction of the type I IFN response during schistosome infection. Moreover, cGAS is important for type I IFN production and phosphorylation of TBK1 and IRF3 in response to stimulation with S. japonicum egg- or adult worm-derived DNA in macrophages. Our results clarified the immunomodulatory effect of cGAS in the regulation of liver granuloma formation during S. japonicum infection, involving sensing schistosome-derived DNA and producing type I IFN. Additionally, we showed that cGAS regulates liver fibrosis in a STING-type I–IFN-independent manner.

Oral squamous cell carcinoma (OSCC) develops through the multistep malignant progression of squamous epithelium. This process can be prevented by PD-1 blockade in a mouse model for oral carcinogenesis. OSCCs exhibit a high incidence of p53 mutations that confer oncogenic gain-of-function (GOF) activities that promote resistance to standard therapies and poor clinical outcomes. To determine whether epithelial p53 mutations modulate anti-PD-1-mediated oral cancer immunoprevention, we generated mouse models for oral carcinogenesis by exposing mice carrying epithelial-specific p53 mutations to the carcinogen 4NQO. Consistent with the oncogenic functions of mutant p53, mice with OSCCs expressing the p53^R172H GOF mutation developed higher metastasis rates than mice with loss-of-function (LOF) p53 deletion or with wild-type p53. Throughout oral cancer progression, pre-invasive and invasive lesions showed a gradual increase in T-cell infiltration, recruitment of immunosuppressive regulatory T-cells (Tregs), and induction of PD-1/PD-L1 immune checkpoint proteins. Notably, while PD-1 blockade prevented the development of OSCCs in mice with wild-type p53 or p53 deletion, GOF p53^R172H abrogated the immunopreventive effects of anti-PD-1, associated with upregulation of IL17 signaling and depletion of exhausted CD8 cells in the microenvironment of the p53^R172H tumors. These findings sustain a potential role for p53 profiling in personalized oral cancer immunoprevention.

A meta‐analysis study to assess the effect of possible risk factors for pharyngocutaneous fistula (PCF) after total laryngectomy of laryngeal carcinoma. A comprehensive literature examination till January 2023 was implemented and 1794 linked studies were appraised. The picked studies contained 3140 subjects with total laryngectomy of laryngeal carcinomas in the picked studies' baseline, 760 of them were PCF, and 2380 were no PCF. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to calculate the consequence of possible risk factors for PCF after total laryngectomy of laryngeal carcinomas and surgical wound infection after total laryngectomy of laryngeal carcinoma by the dichotomous and continuous styles and a fixed or random model. The PCF had a significantly higher surgical wound infection (OR, 6.34; 95% CI, 1.89–21.27, P = .003) compared with the no PCF in total laryngectomy of laryngeal carcinomas. The smoking (OR, 1.73; 95% CI, 1.15–2.61, P = .008), and preoperative radiation (OR, 1.90; 95% CI, 1.37–2.65, P < .001) had significantly higher PCF as a risk factor in total laryngectomy of laryngeal carcinomas. The preoperative radiation had a significantly lower spontaneous PCF closure (OR, 0.33; 95% CI, 0.14–0.79, P = .01) compared with the no preoperative radiation in total laryngectomy of laryngeal carcinomas. However, the neck dissection (OR, 1.34; 95% CI, 0.75–2.38, P = .32), and alcohol intake (OR, 1.95; 95% CI, 0.76–5.05, P = .17), had no significant effect on PCF in total laryngectomy of the PCF had a significantly higher surgical wound infection, and preoperative radiation had a significantly lower spontaneous PCF closure in total laryngectomy of laryngeal carcinomas. Smoking and preoperative radiation were shown to be risk factors for PCF, however, neck dissection and alcohol intake were not shown to be risk factors for PCF in total laryngectomy of laryngeal carcinomas. Although precautions should be taken when commerce with the consequences because some of the picked studies for this meta‐analysis was with low sample sizes.