Journal of Immunology Research最新文献

The biological role of interleukin 17 (IL-17) has been explored during recent decades and identified as a pivotal player in coordinating innate and adaptive immune responses. Notably, IL-17 functions as a double-edged sword with both destructive and protective immunological roles. While substantial progress has implicated unrestrained IL-17 in a variety of infectious diseases or autoimmune conditions, IL-17 plays an important role in protecting the host against pathogens and maintaining physiological homeostasis. In this review, we describe canonical IL-17 signaling mechanisms promoting neutrophils recruitment, antimicrobial peptide production, and maintaining the epithelium barrier integrity, as well as some noncanonical mechanisms involving IL-17 that elicit protective immunity.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer, and the therapy options for PDAC remain restricted. The distinctive tumor immunological microenvironment (TIME) of PDAC, comprising a high number of stromal cells and a limited infiltration of cytotoxic T lymphocytes (CTLs), rendered immunotherapy ineffective. The protein level of ubiquitin-specific protease 43 (USP43) was a prognostic predictor in numerous cancers; however, its function in PDAC is limited. This article focuses on the influence of USP43 expression on PDAC prognosis and TIME alteration.

Methods: Based on TCGA database and tissue microarray staining, the expression of USP43 in PDAC was evaluated. The association between USP43 and prognosis was then investigated using tissue samples and online databases. In PDAC tumor tissues, the correlation between USP43 expression and clinicopathological characteristics, immune cell infiltration, and prognosis was investigated. The expression of USP43 in PDAC cell lines was evaluated using quantitative polymerase chain reaction. Using a cell counting kit-8 (CCK-8) and a cell colony formation test, the viability of the cells was determined. On the basis of online databases and tissue samples, the link between USP43 and immune cell infiltration around PDAC was also examined. For statistical analyses, the software GraphPad, R, and SPSS 26.0 were utilized.

Results: The expression of USP43 was considerably higher in PDAC compared to normal pancreatic tissue in both the TCGA database and the tissue microarrays of PDAC patients (P < 0.001). High USP43 expression was associated with poor overall survival in both the TCGA database and the tissue microarray of PDAC patients (P = 0.046 and 0.021, respectively). USP43 overexpression promoted PANC-1 cell proliferation (P = 0.0018), but USP43 knockdown decreased PANC02 cell proliferation (P < 0.001). According to the TCGA database, USP43 is associated with T cell activation and inhibits CD8⁺ T cell activation in PDAC, as proven by a study of cell lines. Moreover, in both TCGA and PDAC cell lines, USP43 expression was negatively linked with the chemokine signaling pathway.

Conclusions: Overexpression of USP43 is a potential prognostic indicator for PDAC patients. USP43 is a potential biomarker associated with T cell activation, suppression of CD8⁺ T cell enrichment, and the cytokine signal pathway. Future multicenter studies are needed to confirm our findings and their potential application in the treatment of PDAC patients.

Background: Systemic lupus erythematosus (SLE) is characterized by poor regulation of the immune response leading to chronic inflammation and multiple organ dysfunction. Glucocorticoid (GC) is currently one of the main treatments. However, a high dose or prolonged use of GC may result in glucocorticoid-induced osteoporosis (GIOP). Jiedu Quyu Ziyin decoction (JP) is effective in treating SLE and previous clinical studies have proved that JP can prevent and treat SLE steroid osteoporosis (SLE-GIOP). We aim to examine JPs main mechanism on SLE-GIOP through network pharmacology and molecular docking.

Methods: TCMSP and TCMID databases were used to screen potential active compounds and targets of JP. The SLE-GIOP targets are collected from GeneCards, OMIM, PharmGkb, TTD, and DrugBank databases. R software was used to obtain the cross-targets of JP and SLE-GIOP and to perform GO and KEGG enrichment analysis. Cytoscape software was used to make the Chinese Medicines-Active Ingredient-Intersection Targets network diagram. STRING database construct protein-protein interaction network and obtain the core targets. Auto Dock Tools and Pymol software were used for docking.

Results: Fifty eight targets overlapped between JP and SLE-GIOP were suggested as potential targets of JP in the treatment of SLE-GIOP. Network topology analysis identified five core targets. GO enrichment analysis was obtained 1,968 items, and the top 10 biological process, closeness centrality, and molecular function were displayed. A total of 154 signaling pathways were obtained by KEGG enrichment analysis, and the top 30 signaling pathways were displayed. JP was well bound by MAPK1, TP53, and MYC according to the molecular docking results.

Conclusion: We investigated the potential targets and signaling pathways of JP against SLE-GIOP in this study. It shows that JP is most likely to achieve the purpose of treating SLE-GIOP by promoting the proliferation and differentiation of osteoblasts. A solid theoretical foundation will be provided for the future study of clinical and experimental topics.

Background: Pancreatic cancer (PC) is a malignant cancer with poor prognosis and high mortality rate. Sine oculis homeobox homolog 1 (SIX1) participates in the development of many cancers. However, the function of SIX1 in PC is not fully understood.

Methods: SIX1 expression was determined using immunohistochemistry in PC tissues and cell lines. Glucose consumption, lactate production, and ATP assays were used to detect the function of SIX1. PC cells and NK cells were cocultured to study the effect of SIX1 overexpression in PC cells on NK cell function. Chromatin immunoprecipitation (ChIP) assays were used to study the relationship between SIX1 and lactate dehydrogenase A (LDHA). A series of in vitro and in vivo assays were further applied to elucidate the important role of the SIX1/LDHA axis in metabolism and NK cell dysfunction in PC.

Results: SIX1 was significantly upregulated in PC tissue; SIX1 overexpression promoted the glycolysis capacity of PANC-1 and CFPAC-1 cells and resulted in NK cell dysfunction after the NK cells had been cultured with PC cells. LDHA inhibitor partially restored the promotion of PC caused by SIX1 overexpression. According to ChIP assays, SIX1 directly binds to the LDHA promoter region. Moreover, LDHA inhibitor and lactate transporter blocker treatment promoted the function of NK cells cocultured with PC cells. In vivo experiments yielded the same results.

Conclusion: The SIX1/LDHA axis promotes lactate accumulation and leads to NK cell dysfunction in PC.

Patients bearing liver metastasis of pancreatic adeno carcinoma (PDAC) suffer from poor prognosis due to its short duration and high mortality. Complex tumor microenvironment (TME) exists in liver metastatic niches, and tumor-associated macrophages (TAMs) have play vital roles in metastasis generation and outgrowth. We have discovered that M2 type TAM-derived SEMA5A could bind to its tumor cell-expressed receptor PLXNB3 to promote tumor cell proliferation and outgrowth. We utilized liver metastasis samples of PDAC patients, intrasplenic injection mouse models, and Kras ^G12D/Trp53 ^R172H/Pdx1-Cre (KPC) mouse models for in vivo study. In mechanism investigation, we have discovered that SEMA5A-PLXNB3 axis could achieve tumor cell proliferation and survival via enhancing aerobic glycolysis termed as the Warburg effects. Targeting this axis may be a potential therapeutic approach for PDAC patients with unresectable liver metastasis.

Specific biomarkers of intestinal injury associated with necrotizing enterocolitis (NEC) are needed to diagnose and monitor intestinal mucosal injury and recovery. This study aims to develop and test a modified enzyme-linked immunosorbent assay (ELISA) protocol to detect the total keratin 8 (K8) in the stool of newborns with NEC and investigate the clinical value of fecal K8 as a marker of intestinal injury specifically associated with NEC. We collected fecal samples from five newborns with NEC and five gestational age-matched premature neonates without NEC at the Lucile Packard Children's Hospital Stanford and Washington University School of Medicine, respectively. Fecal K8 levels were measured using a modified ELISA protocol and Western blot, and fecal calprotectin was measured using a commercial ELISA kit. Clinical data, including gestational age, birth weight, Bell stage for NEC, feeding strategies, total white blood cell (WBC) count, and other pertinent clinical variables, were collected and analyzed. Fecal K8 levels were significantly higher in the pre-NEC group (1-2 days before diagnosis of NEC) and NEC group than those in the non-NEC group (p = 0.013, p = 0.041). Moreover, fecal K8 was relatively higher at the onset of NEC and declined after the resolution of the disease (p = 0.019). Results with similar trends to fecal K8 were also seen in fecal calprotectin (p = 0.046), but not seen in total WBC count (p = 0.182). In conclusion, a modified ELISA protocol for the total K8 protein was successfully developed for the detection of fecal K8 in the clinical setting of premature newborns with NEC. Fecal K8 is noted to be significantly increased in premature newborns with NEC and may, therefore, serve as a noninvasive and specific marker for intestinal epithelial injury associated with NEC.

Background: Systemic inflammation may be involved in the entire cancer process as a promoter and is associated with antitumor immunity. The systemic immune-inflammation index (SII) has been shown to be a promising prognostic factor. However, the relationship between SII and tumor-infiltrating lymphocytes (TIL) have not been established in esophageal cancer (EC) patients receiving concurrent chemoradiotherapy (CCRT).

Methods: Retrospective analysis of 160 patients with EC was performed, peripheral blood cell counts were collected, and TIL concentration was assessed in H&E-stained sections. Correlations of SII and clinical outcomes with TIL were analyzed. Cox proportional hazard model and Kaplan-Meier method were used to perform survival outcomes.

Results: Compared with high SII, low SII had longer overall survival (OS) (P = 0.036, hazard ratio (HR) = 0.59) and progression-free survival (PFS) (P = 0.041, HR = 0.60). Low TIL showed worse OS (P < 0.001, HR = 2.42) and PFS (P < 0.001, HR = 3.05). In addition, research have shown that the distribution of SII, platelet-to-lymphocyte ratio, and neutrophil-to-lymphocyte ratio were negatively associated with the TIL state, while lymphocyte-to-monocyte ratio presented a positive correlation. Combination analysis observed that SII^low + TIL^high had the best prognosis of all combinations, with a median OS and PFS of 36 and 22 months, respectively. The worst prognosis was identified as SII^high + TIL^low, with a median OS and PFS of only 8 and 4 months.

Conclusion: SII and TIL as independent predictors of clinical outcomes in EC receiving CCRT. Furthermore, the predictive power of the two combinations is much higher than a single variable.