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[en] This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of authors. The Journal received an expression of concern from a reader, which noted that: “The problem is that there is no IL-26 gene in the mouse. They claim they bought the KO mouse and the mouse IL-26 protein but given that there is no mouse IL-26 gene, a purchase is not possible and in fact no such reagents are available. Furthermore they do reference and anti-IL-26 antibody but the spec sheet clearly states that it is only reactive with the human protein…., the Enzo Life Sciences online catalog does not have a listing for recombinant IL-26 of any kind.” The authors apologize for their mistakes and have asked to retract the article.
[en] Peroxisome proliferator-activated receptor gamma (PPARγ) and miR-124 have been reported to play important roles in regulation of inflammation. However, the underlying anti-inflammatory mechanisms remain not well understood. In the present study, we demonstrated that the expression level of PPARγ is positively correlated with that of miR-124 in patients with sepsis. Activation of PPARγ upregulates miR-124 and in turn inhibits miR-124 target gene. PPARγ bound directly to PPRE in the miR-124 promoter region, and enhanced the promoter transcriptional activity. PPARγ-induced miR-124 is involved in the suppression of pro-inflammatory cytokine in vitro and in vivo. These results suggest that PPARγ-induced miR-124 inhibits the production of pro-inflammatory cytokines is a novel PPARγ anti-inflammatory mechanism and also indicate that miR-124 may be a potential therapeutic target for the treatment of inflammatory diseases. - Highlights: • The expression level of PPARγ is positively correlated with that of miR-124 in patients with sepsis. • PPARγ upregulates miR-124 and in turn inhibits miR-124 target gene. • PPARγ promotes miR-124 transcription through binding to miR-124 promoter region. • Inhibition of miR-124 attenuates the PPARγ-mediated suppression of proinflammatory cytokines in vitro. • PPARγ-induced miR-124 is involved in the suppression of pro-inflammatory cytokine in vivo.
[en] Adoptive immunotherapy using chimeric antigen receptors-modified T cells (CAR-T) is a promising approach for cancer treatment. However, CARs currently applied in the clinics cannot be effectively regulated and the safety of CAR-T cell therapies remains a major concern. To improve the safety of CAR-T cells, we designed a synthetic splitting CAR (ssCAR) that can regulate T cell functions exogenously. Epidermal growth factor receptor variant III (EGFRvIII) was used as a molecular target for ssCAR. Our results indicate that both EGFRvIII and small molecule are needed for the activation of the ssCAR-T cells. AP21967 dose-dependently increased the expression of T cell activation, production of cytokines and extent of cell lysis. In conclusion, the gene switch designed in this study allows for temporal and spatial control over engineered T cells in a dose-and time-dependent manner by AP21967. Our work demonstrates the feasibility and improved safety profile of this novel treatment approach.
[en] Acute inflammation can cause serious tissue damage and disease in physiologically-challenged organisms. The precise mechanisms leading to these detrimental effects remain to be determined. In this study, we utilize a reproducible means to induce cellular immune activity in Drosophila larvae in response to mechanical stress. That is, forceps squeeze-administered stress induces lamellocytes, a defensive hemocyte type that normally appears in response to wasp infestation of larvae. The posterior signaling center (PSC) is a cellular microenvironment in the larval hematopoietic lymph gland that is vital for lamellocyte induction upon parasitoid attack. However, we found the PSC was not required for mechanical stress-induced lamellocyte production. In addition, we observed that mechanical injury caused a systemic expression of Unpaired3. This cytokine is both necessary and sufficient to activate the cellular immune response to the imposed stress. These findings provide new insights into the communication between injured tissues and immune system induction, using stress-challenged Drosophila larvae as a tractable model system.
[en] Highlights: • Glycyrrhizin (Gly) represses LPS-induced microglial activation without cell toxicity. • Glycyrrhizin dose-dependently inhibits LPS-triggered inflammatory response. • Elevation of HMGB1 reverses glycyrrhizin-inhibited inflammatory response in microglia. • HMGB1-mediated TLR4-NF-κB activation account for gly-restrained inflammation. • Gly alleviates CFA-induced pain hypersensitivity, inflammation, microglia activation. Chronic inflammatory pain is a severe clinical problem that greatly affects patients’ quality of life and causes huge economic burden. Microglia-mediated neuroinflammation exerts critical roles in the pathogenic progression of inflammatory pain. Recent evidence corroborates the anti-inflammatory and neuroprotective efficacy of glycyrrhizin; however, its function in inflammatory pain remains poorly elucidated. In the present study, glycyrrhizin suppressed LPS-induced activation of microglial cell BV2 by inhibiting NO production and expression of microglial marker IBA-1. Intriguingly, LPS-induced high expression and generation of inflammatory cytokines (i.e., IL-6, TNF-α and IL-1β) was notably reversed by glycyrrhizin pre-treatment. Mechanistic analysis confirmed that high expression of high-mobility group box 1 (HMGB1) in LPS-activated microglia was inhibited following glycyrrhizin. More importantly, restoring HMGB1 expression by recombinant adenovirus vector of Ad-HMGB1 counteracted glycyrrhizin-restrained inflammatory response in microglia upon LPS stimulation. Furthermore, glycyrrhizin dampened the activation of subsequent TLR4-NF-κB pathway in LPS-stimulated microglia, which was abrogated by HMGB1 elevation. Furthermore, blocking this pathway by si-TLR4 transfection reversed the effects of HMGB1 overexpression on the inhibitor roles of glycyrrhizin in microglia-triggered inflammation. Additionally, glycyrrhizin administration also alleviated CFA-evoked mechanical allodynia and thermal hyperalgesia in inflammatory pain model of mice, concomitant with suppression in inflammatory response and microglial activation. Simultaneously, elevation of HMGB1, TLR4 and p65-NF-κB protein expression induced by CFA injection was also abrogated after glycyrrhizin. Accordingly, this study reveal that glycyrrhizin may act as a promising therapeutic avenue for the treatment of inflammatory pain.
[en] Glioblastoma multiforme (GBM) is the most lethal and aggressive type of primary brain malignancy. Failures of the traditional therapies in treating GBMs raise the urgent requirement to develop new approaches with more responsive targets. The phenomenon of the high infiltration of tumor-associated macrophages (TAMs) into GBMs has been observed for a long time. Regardless of the limited knowledge about TAMs, the high percentage of supportive TAM in GBM tumor mass makes it possible to be a good target for GBM treatment. In this review, we discussed the unique features of TAMs in GBMs, including their origin, the tumor-supportive properties, the secreted cytokines, and the relevant mechanisms. In addition, we tried to interpret the current understandings about the interplay between GBM cancer cells and TAMs. Finally, the translational studies of targeting TAMs were also described
[en] Highlights: • Rnf112−/− mice exhibits accelerated brain injury and neuroinflammation. • Rnf112−/− promotes inflammation by enhancing TLR-4/NF-κB pathway. • Over-expressing Rnf112 attenuates brain injury after intracerebral hemorrhage. Intracerebral hemorrhage (ICH) is reported as a common and often fatal type of stroke accompanied with high morbidity and mortality, and it frequently results in long-lasting neurological dysfunctions. However, the pathogenesis that contributes to ICH has not been fully understood. Rnf112, also known as Znf179, is a member of the RING finger protein family. The expression of Rnf112 is abundant in the brain and is modulated during brain progression and development. The study aimed to explore the role of Rnf112 in brain injury after ICH, as well as the underlying molecular mechanisms. The results indicated that ICH led to a significant decrease in Rnf112, which was confirmed in oxyhemoglobin (oxyHb)-incubated astrocytes and microglial cells. Moreover, the Rnf112 knockout (Rnf112−/−) mice and wild type (WT) mice induced by ICH were further employed. Compared to the WT/ICH group, Rnf112−/− mice exhibited accelerated brain injury, as evidenced by the increased brain water contents and neurological deficit scores (NDS). In comparison to WT/ICH group, a remarkable up-regulation in the release of pro-inflammatory cytokines, including tumor necrotic factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β, was observed in perihematoma tissues of Rnf112−/− mice on day 3 post-ICH. The process was along with promoted glial fibrillary acidic protein (GFAP) and Iba1 expression and reduced NeuN levels. Furthermore, ICH-induced increases in toll-like receptor (TLR)-4 and myeloid differentiation primary response protein (MyD88) expression were exacerbated by the loss of Rnf112. The phosphorylated expression of IKKα, inhibitor of NF-κB (IκBα) and nuclear factor-kappa B (NF-κB) induced by ICH in perihematoma tissues of mice was markedly enhanced in Rnf112−/− mice. Rnf112 repression-induced inflammatory response was verified in lipopolysaccharide (LPS)-incubated glial cells. In contrast, over-expressing Rnf112 markedly attenuated ICH-induced brain injury by restraining inflammation via inactivating TLR-4/NF-κB pathway. In summary, our findings suggested that Rnf112 expression was highly involved in the progression of ICH, and targeting Rnf112 signaling might be a promising therapeutic strategy against ICH development.
[en] Highlights: • TREM2, Arginase-1 and proinflammatory cytokines increased in the midbrain of PD mice. • Knockdown of TREM2 in BV2 microglia exaggerated M1 microglial inflammatory responses. • TREM2 overexpression promoted M2 polarization and alleviated microglial inflammation. • TREM2 plays a crucial role in altering M1 microglia to M2 phenotype. Neuroinflammation and overactivated microglia underlies the pathogenesis of Parkinson's disease (PD). Furthermore, microglia could polarize into classic inflammatory M1 and immunosuppressive M2 phenotype. Thus, inhibiting the overactivated inflammatory M1 microglia by promoting the transformation of microglia to the protective M2 phenotype provides potential therapy for PD, but the mechanism that modulates microglia polarization remains unknown. Triggering receptor expressed on myeloid cells-2 (TREM2) is a recently identified immune receptor expressed by the microglia in the brain. Emerging evidence indicates that TREM2 enhances the phagocytosis function of microglia and suppress inflammation. Based on these evidence, we hypothesized that TREM2 might play a protective role through regulating microglia polarization. Here, we employ a lentiviral strategy to overexpress or suppress TREM2 on microglia and found that TREM2 was essential for M2 microglia polarization. Knockdown of TREM2 in BV2 microglia inhibited M2 polarization and lead to exaggeration of M1 microglial inflammatory responses, whereas overexpression of TREM2 promoted M2 polarization and alleviated microglial inflammation. We also observed that the TREM2 level was higher in the midbrain of PD mice, which was accompanied by an elevated level of Arginase-1 and increased proinflammatory cytokines, suggesting that TREM2 is an important factor in switching the microglia phenotypes. Taken together, these findings indicate that TREM2 plays a crucial role in altering the proinflammatory M1 microglia to M2 phenotype and has beneficial effects in the immune pathogenesis of PD.
[en] Highlights: • Interleukin-22 and its receptor (IL22R1) are upregulated after hindlimb ischemia. • Loss of IL-22 by mAb reduced angiogenesis. • IL-22 overexpression improved angiogenesis after hindlimb ischemia. Inflammation induced by muscle ischemia is involved in tissue repair and perfusion recovery in peripheral arterial disease (PAD) patients. Interleukin (IL)-22 is an inflammatory cytokine discovered in recent years and shows versatile functions; however, its role in PAD remains unknown. Here, we test whether IL-22 and its receptors are involved in angiogenesis in experimental PAD.
[en] Cancer, a major health problem, affects 12 million people worldwide every year. With surgery and chemo-radiation the long term survival rate for the majority of cancer patients is dismal. Thus novel treatments are urgently needed. Immunotherapy, the harnessing of the immune system to destroy cancer cells is an attractive option with potential for long term anti-tumor benefit. Cytokines are biological response modifiers that stimulate anti-tumor immune responses. In this review, we discuss the anti-tumor efficacy of the chemotactic cytokine CCL21 and its pre-clinical and clinical application in cancer