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Background and Purpose: Macrophages regulate iron homeostasis in the liver and play important role in hepatic ischaemia/reperfusion (I/R) injury. This study investigates the role of macrophages in iron overload-related hepatocyte damage during liver I/R. Experimental Approach: Liver biopsies from patients undergoing partial hepatectomy with or without hepatic portal occlusion were recruited and markers of hepatocyte cell death and macrophage extracellular traps (METs) were detected.A murine hepatic I/R model was also established in high-iron diet-fed mice.Ferrostatin-1 and deferoxamine were administered to investigate the role of ferroptosis in hepatic I/R injury. The macrophage inhibitor liposome-encapsulated clodronate was used to investigate the interaction between macrophages and ferroptosis. AML12 hepatocytes and RAW264.7 macrophages were cocultured in vitro. An inhibitor of macrophage extracellular traps was used to evaluate the role and mechanism of these traps and ferroptosis in hepatic I/R injury.Key Results: Hepatocyte macrophage extracellular trap formation and ferroptosis were greater in patients who underwent hepatectomy with hepatic portal occlusion and in mice subjected to hepatic I/R. Macrophage extracellular traps increased when macrophages were subjected to hypoxia/reoxygenation and when they were cocultured with hepatocytes. Ferroptosis increased and post-hypoxic hepatocyte survival decreased, which were reversed by inhibition of macrophage extracellular traps.Ferroptosis inhibition attenuated post-ischaemic liver damage. Moreover, iron overload induced hepatic ferroptosis and exacerbated post-ischaemic liver damage, which were reversed by the iron chelator. Conclusion and Implications:Macrophage extracellular traps are in volved in regulating ferroptosis highlighting the therapeutic potential of macrophage extracellular traps and ferroptosis inhibition in reducing liver I/R injury.

The morbidity and mortality of sepsis-induced acute kidney injury (SAKI) remain high. Early detection using molecular ultrasound imaging may reduce mortality and improve the prognosis. Inspired by the intrinsic relationship between platelets and SAKI, platelet membrane-coated hybrid microbubbles (Pla-MBs) are designed for early recognition of SAKI. Pla-MBs are prepared by ultrasound-assisted recombination of liposomes and platelets, consisting of inherent platelet membrane isolated from platelets. By coating with platelet membranes, Pla-MBs are endowed with various adhesive receptors (such as integrin 𝜶IIb𝜷3), providing a benefit for selective adhesion to damaged endothelium in SAKI. In a rat SAKI model, by combining the advantages of molecular ultrasound imaging and platelet membrane, Pla-MBs display platelet-mimicking properties and achieve the early targeted diagnosis of SAKI prior to the regular laboratory markers of kidney function. Moreover, the expression of platelet-binding proteins (von Willebrand factor and fibrinogen) in the kidneys shows consistent results with molecular ultrasound imaging. Together, microbubble functionalization with platelet membranes is diagnostically beneficial for SAKI and might be a promising modality for endothelial injury diseases in the future.

Acute kidney injury (AKI) occurs in half of patients with septic shock, resulting in unacceptably high mortality. However, effective preventive treatments are still lacking. We hypothesized that pretreatment with lipoxin A4 (LXA4), known to promote inflammation resolution, may attenuate septic AKI via blocking crosstalk between inflammation and cellular senescence. In this study, rats developed AKI following cecal ligation and puncture (CLP), as evidenced by a dynamic increase in serum creatinine, blood urea nitrogen, urinary kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and pathological injury, accompanied by increased levels of inflammation (IL-6, TNF-α, and HMGB1) and tubular cell senescence. While, on the one hand, inhibition of senescence with rapamycin restored renal function and attenuated septic inflammatory response, on the other hand, LXA4 administration inhibited renal inflammation and tubular epithelial cell senescence after CLP. Ultimately, pretreatment with LXA4 significantly restored renal function and increased the survival rate of rats after CLP. Furthermore, LXA4 inhibited NF-κB-mediated inflammatory response and the p53/p21 senescence pathway in vivo and in vitro. However, the effect was reversed by PPAR-γ siRNA and antagonist. These results indicated that LXA4 exerted its renoprotective effects by blocking the crosstalk between inflammation and premature senescence in a PPAR-γ-dependent manner. Our findings also suggested that premature senescence plays a critical role in septic AKI and that inhibition of the crosstalk between inflammation and premature senescence may represent a new and major mechanism through which LXA4 attenuates septic AKI.

Allergic asthma is a chronic inflammatory disease mediated by Th2 cell immune responses. Currently, immunotherapies based on immune deviation are attractive, preventive, and therapeutic strategies for asthma. Many studies have shown that intracellular bacterial infections such as mycobacteria and their components can suppress asthmatic reactions by enhancing Th1 responses, while helminth infections and their proteins can inhibit allergic asthma via immune regulation. However, some helminth proteins such as SmP40, the major egg antigen of Schistosoma mansoni, are found as Th1 type antigens. Using a panel of overlapping peptides, we identified T-cell epitopes on SjP40 protein of Schistosoma japonicum, which can induce Th1 cytokine and inhibit the production of Th2 cytokines and airway inflammation in a mouse model of allergic asthma. These results reveal a novel form of immune protective mechanism, which may play an important role in the modulating effect of helminth infection on allergic asthmatic reactions.Keywords: Asthma r peptides r Schistosoma japonicum r SjP40 r Th1 epitope Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAllergic asthma is a chronic airway disorder characterized by reversible airflow obstruction, increased allergen-specific IgE production, and predominant eosinophilic airway inflammation [1]. From immunology point of view, the pathology in asthma occurs Correspondence: Dr. Peimei Liu e-mail: liupeimei63@126.com as a consequence of increased Th2 type immune responses, especially overproduction of IL-4, IL-5, and IL-13 by allergen-specific CD4 + T helper (Th) cells [2,3].The prevalence of allergy and asthma has increased markedly over the past decades world-wide, not only in developed but also developing areas [4,5]. The reason for this dramatic increase * These authors contributed equally to this work. Eur. J. Immunol. 2016Immunol. . 46: 1203Immunol. -1213 remains unclear. It was believed that an insufficient stimulation of the Th1 responses due to limited exposure to bacterial and viral pathogens could not counterbalance the expansion of Th2 responses resulting in predisposition of allergy. However, the distorted Th1/Th2 balance could not explain the simultaneous increase in several Th1-mediated auto-immune diseases together with the increase in allergic disorders in the same countries. Then it is suggested that more vital microbial exposures, such as chronic infections (helminthes) and commensals seem to be important to prevent the development of hyperinflammatory responses [6]. Therefore, the induction of a strong regulatory network (tolerogenic DC, Treg, Breg, Tr-1, Tr-3) and Th1 responses by these microbes is an important factor in controlling the diseases.Immunotherapy based on immune deviation is an effective strategy to treat or prevent allergic asthma. Live and dead bacteria, parasite, or bacterial components such as purified protein derivative from Mycobacterium tuberculosis have shown potential to prote...

This study mainly investigated the effect of matrine on TNBS-induced intestinal inflammation in mice. TNBS treatment caused colonic injury and gut inflammation. Matrine (1, 5, and 10 mg/kg) treatment alleviated colonic injury and gut inflammation via reducing bleeding and diarrhea and downregulating cytokines expression (IL-1β and TNF-α). Meanwhile, serum immunoglobulin G (IgG) was markedly reduced in TNBS treated mice, while 5 and 10 mg/kg matrine alleviated IgG reduction. Fecal microbiota was tested using 16S sequencing and the results showed that TNBS caused gut microbiota dysbiosis, while matrine treatment markedly improved gut microbiota communities (i.e., Bacilli and Mollicutes). Functional analysis showed that cell motility, nucleotide metabolism, and replication and repair were markedly altered in the TNBS group, while matrine treatment significantly affected cell growth and death, membrane transport, nucleotide metabolism, and replication and repair. In conclusion, matrine may serve as a protective mechanism in TNBS-induced colonic inflammation and the beneficial effect may be associated with gut microbiota.

Background:Ulcerative colitis (UC) is associated with differential expression of genes involved in inflammation and tissue remodeling, including FOXO3a, which encodes a transcription factor known to promote inflammation in several tissues. However, FOXO3a expression in tissues affected by UC has not been examined. This study investigated the effects of FOXO3a on UC pathogenesis.Methods:FOXO3a expression, in 23 patients with UC and in HT29 cells treated with tumor necrosis factor-α (TNF-α) for various durations, was detected by quantitative real-time polymerase chain reaction and Western blotting analysis. Enzyme-linked immunosorbent assay was used to quantify interleukin (IL)-8 expression in FOXO3a-silenced HT29 cells treated with TNF-α for various durations.Results:The messenger RNA and protein expression of FOXO3a were significantly lower in UC tissues than those in normal subjects (P < 0.01). TNF-α treatment for 0, 0.5, 1, 6, and 24 h induced FOXO3 degradation in HT29 cells. FOXO3a silencing increased IL-8 levels in HT29 cells treated with TNF-α for 6 h (P < 0.05).Conclusion:FOXO3a may play an important role in the intestinal inflammation of patients with UC.

Ulcerative colitis (UC), which is a type of inflammatory bowel disease, is a chronic intestinal disorder of multifactorial etiology. Numerous studies have indicated an association between UC and intestinal bacteria. However, a limited number of studies regarding the expression of interleukin-17 (IL-17) and interleukin-23 (IL-23) in association with intestinal bacteria have been performed. The aim of the current study was to investigate the gut microbiota alterations in patients with UC, at a number of taxonomic levels, and their relationship with intestinal inflammation by analyzing the protein expression of IL-17 and IL-23. Specimens were collected from 10 healthy controls and 16 patients with UC. A histological examination was performed in colonic tissues, IL-17 and IL-23 protein expression was detected by immunohistochemistry, fecal samples were sequenced using 16S rDNA sequencing and bioinformatics analysis was performed. The UC group exhibited an increased histological score (P<0.01) and upregulated IL-17 and IL-23 expression (P<0.01). At the order level, the bacterial diversity of the UC group was decreased. β-diversity analyses, including principal component analysis, principal coordinate analysis and non-metric multidimensional scaling, demonstrated that the two groups of samples were separated into two taxonomic categories, as distinct variations were observed in the analysis of group differences (P=0.001). Regarding the differences in species composition between the groups, Enterococcus was indicated to be the species with the greatest difference in abundance compared with the healthy control group (P<0.01), followed by Lactobacillus (P<0.05), Escherichia-Shigella (P<0.05), Bifidobacterium and Bacteroides. In addition, the average optical density of IL-17 was positively correlated with the histological score (ρ= 0.669; P= 0.035), Enterococcus (r= 0.843; P<0.001), Lactobacillus (r= 0.737; P= 0.001), Bifidobacterium (r= 0.773; P<0.001) and Escherichia-Shigella (r=0.663; P=0.005), and the average optical density of IL-23 was positively correlated with the histological score (ρ= 0.733; P= 0.016), Enterococcus (r= 0.771; P<0.001), Lactobacillus (r= 0.566; P= 0.022), Bifidobacterium (r= 0.517; P= 0.041) and Escherichia-Shigella (r= 0.613; P= 0.012). The results of the present study indicated that the intestinal microbiota of patients with UC differed from that of healthy controls at multiple taxonomic levels. The alterations of the intestinal microflora were closely associated with the degree of inflammation. The IL-23/IL-17 axis, as a key factor in the development of UC, maybe associated with the alterations of intestinal microflora. The interaction between intestinal microflora and the IL-23/IL-17 axis may serve an important role in the pathogenesis of UC.