BackgroundGenerally, febrile patients admitted to the Department of Infectious Diseases, Fudan University Affiliated Huashan Hospital, China may eventually be diagnosed as infectious (ID) or non-infectious inflammatory diseases (NIID). Furthermore, mortality from sepsis remains incredibly high. Thus, early diagnosis and prognosis evaluation of sepsis is necessary. Here, we investigated neutrophil (n)CD64 index profile in a cohort of febrile patients and explored its diagnostic and prognostic value in ID and NIID.MethodsThis observational cohort study enrolled 348 febrile patients from the Emergency Department and Department of Infectious Diseases. nCD64 index were detected using flow cytometry, and dynamically measured at different timepoints during follow-up. Procalcitonin (PCT), C-reactive protein (CRP), and ferritin levels were measured routinely. Finally, the diagnostic and prognostic value of nCD64 index were evaluated by receiver operating characteristic (ROC) analysis and Kaplan-Meier curve analysis.ResultsOf included 348 febrile patients, 238, 81, and 29 were categorized into ID, NIID, and lymphoma groups, respectively. In ID patients, both SOFA score and infection site had impact on nCD64 index expression. In NIID patients, adult-onset Still’s disease patients had the highest nCD64 index value, however, nCD64 index couldn’t distinguish between ID and NIID. Regardless of the site of infection, nCD64 index was significantly higher in bacterial and viral infections than in fungal infections, but it could not discriminate between bacterial and viral infections. In bloodstream infections, gram-negative (G-) bacterial infections showed an obvious increase in nCD64 index compared to that of gram-positive (G+) bacterial infections. nCD64 index has the potential to be a biomarker for distinguishing between DNA and RNA virus infections. The routine measurement of nCD64 index can facilitate septic shock diagnosis and predict 28-day hospital mortality in patients with sepsis. Serial monitoring of nCD64 index in patients with sepsis is helpful for evaluating prognosis and treatment efficacy. Notably, nCD64 index is more sensitive to predict disease progression and monitor glucocorticoid treatment in patients with NIID.ConclusionsnCD64 index can be used to predict 28-day hospital mortality in patients with sepsis and to evaluate the prognosis. Serial determinations of nCD64 index can be used to predict and monitor disease progression in patients with NIID.

Canonical transient receptor potential‐6 (TRPC6) has been reported to be involved in cell damage after ischemia/reperfusion (I/R) injury in target organs. While the effect and of TRPC6 on pyroptosis in renal I/R injury remain unclear. In our study, we first established the renal I/R mouse model and oxygen–glucose deprivation and re‐oxygenation (OGD/R) cell model, and investigated the impacts of TRPC6 on the pyroptosis‐related proteins using CCK‐8, western blot, ELISA, and immunofluorescence probes. Besides, we also explored the mechanism of TRPC6 in pyroptosis of renal tubular epithelial cells through A20 knockdown or overexpression and zinc chloride (ZnCl2) or a zinc ion chelator (TPEN) treatment. Our results indicated that I/R injury could cause downregulation of TRPC6 both in vivo and in vitro. In the I/R injury murine model, TRPC6 inhibition exacerbated tissue damage and upregulated NLRP3, ASC, caspase‐1, IL‐18, and IL‐1β, which could be alleviated by the administration of ZnCl2. In the OGD/R cell model, inhibitor of TRPC6 (SAR7334) reduced zinc ion influx, aggravated cell death and upregulated pyroptosis‐related protein. The pyroptosis phenotype also could be alleviated by ZnCl2 and intensified by TPEN. Overexpression of A20 reduced the expression of pyroptosis‐related protein, increased cell viability in the sh‐TRPC6 and TPEN‐treated OGD/R cell models, while A20 deficiency impaired the protective effect of zinc ion. Therefore, our results indicate that TRPC6 could promote zinc ion influx in renal tubular epithelial cells, thereby upregulating intracellular A20, inhibiting the activation of inflammasome NLRP3, and ultimately attenuating renal I/R injury.

Sepsis represents a syndrome of systemic inflammatory response, which is mostly a result of infection with various pathogenic microorganisms, characterized by an uncontrolled infection response of the organism leading to life-threatening organ dysfunction. Long noncoding RNA (lncRNA), as competing endogenous RNA, can affect the binding of microRNA (miRNA) to mRNA, thus influencing the development of sepsis. In this study, based on transcriptome data from GEO database, we screened differentially expressed lncRNAs and constructed lncRNA-miRNA-mRNA network. And pathway IL-17RA-1/miR-7847-3p/protein kinase C gamma (PRKCG) coexpression network was successfully sorted out. The effect of this network on LPS-induced sepsis model in THP-1 cells was also verified by CCK-8, scratch, ELISA, Western blot, and qRT-PCR assays. Corresponding binding sites of miR-7847-3p to IL-17RA-1 and miR-7847-3p to PRKCG were verified using dual luciferase gene reporter assays, respectively. Compared with control, si-IL-17RA-1 significantly inhibited the cell viability and migration ability of THP-1, and levels of proinflammatory factors IL-6, IL-1β, and TNF-α secreted were markedly decreased, and the expression of IL-17RA-1, PRKCG, p-MEKK1, and p-JNK were markedly reduced. In addition, IL-17RA-1 could target binding to miR-7847-3p and inhibit its expression, and miR-7847-3p could also bind to PRKCG. Our experiments demonstrate that IL17-RA-1 attenuates the sepsis response through the miR-7847-3p/MAPK pathway, and this competing endogenous RNA (ceRNA) network may be a potential approach to predict and combat sepsis.