Efficacy of Genotype-matched Vaccine Against Re-emerging Genotype V Japanese Encephalitis Virus.

Japanese encephalitis (JE), caused by the Japanese encephalitis virus (JEV), is a highly threatening disease with no specific treatment. Fortunately, the development of vaccines has enabled effective defense against JE. However, re-emerging genotype V (GV) JEV poses a challenge as current vaccines are genotype III (GIII)-based and provide suboptimal protection. Given the isolation of GV JEVs from Malaysia, China, and the Republic of Korea, there is a concern about the potential for a broader outbreak. Under the hypothesis that a GV-based vaccine is necessary for effective defense against GV JEV, we developed a pentameric recombinant antigen using cholera toxin B as a scaffold and mucosal adjuvant, which was conjugated with the E protein domain III of GV by genetic fusion. This GV-based vaccine antigen induced a more effective immune response in mice against GV JEV isolates compared to GIII-based antigen and efficiently protected animals from lethal challenges. Furthermore, a bivalent vaccine approach, inoculating simultaneously with GIII- and GV-based antigens, showed protective efficacy against both GIII and GV JEVs. This strategy presents a promising avenue for comprehensive protection in regions facing the threat of diverse JEV genotypes, including both prevalent GIII and GI as well as emerging GV strains.

PRKCSH contributes to TNFSF resistance by extending IGF1R half-life and activation in lung cancer.

Tumor necrosis factor superfamily (TNFSF) resistance contributes to the development and progression of tumors and resistance to various cancer therapies. Tumor-intrinsic alterations involved in the adaptation to the TNFSF response remain largely unknown. Here, we demonstrate that protein kinase C substrate 80K-H (PRKCSH) abundance in lung cancers boosts oncogenic IGF1R activation, leading to TNFSF resistance. PRKCSH abundance is correlated with IGF1R upregulation in lung cancer tissues. Specifically, PRKCSH interacts with IGF1R and extends its half-life. The PRKCSH-IGF1R axis in tumor cells impairs caspase-8 activation, increases Mcl-1 expression, and inhibits caspase-9, leading to an imbalance between cell death and survival. PRKCSH deficiency augmented the antitumor effects of natural killer (NK) cells, representative TNFSF effector cells, in a tumor xenograft IL-2Rg-deficient NOD/SCID (NIG) mouse model. Our data suggest that PRKCSH plays a critical role in TNFSF resistance and may be a potential target to improve the efficacy of NK cell-based cancer therapy.

Newly isolated Lactobacillus paracasei strain modulates lung immunity and improves the capacity to cope with influenza virus infection.

BACKGROUND: The modulation of immune responses by probiotics is crucial for local and systemic immunity. Recent studies have suggested a correlation between gut microbiota and lung immunity, known as the gut-lung axis. However, the evidence and mechanisms underlying this axis remain elusive. RESULTS: In this study, we screened various Lactobacillus (L.) strains for their ability to augment type I interferon (IFN-I) signaling using an IFN-α/ß reporter cell line. We identified L. paracasei (MI29) from the feces of healthy volunteers, which showed enhanced IFN-I signaling in vitro. Oral administration of the MI29 strain to wild-type B6 mice for 2 weeks resulted in increased expression of IFN-stimulated genes and pro-inflammatory cytokines in the lungs. We found that MI29-treated mice had significantly increased numbers of CD11c+PDCA-1+ plasmacytoid dendritic cells and Ly6Chi monocytes in the lungs compared with control groups. Pre-treatment with MI29 for 2 weeks resulted in less weight loss and lower viral loads in the lung after a sub-lethal dose of influenza virus infection. Interestingly, IFNAR1-/- mice did not show enhanced viral resistance in response to oral MI29 administration. Furthermore, metabolic profiles of MI29-treated mice revealed changes in fatty acid metabolism, with MI29-derived fatty acids contributing to host defense in a Gpr40/120-dependent manner. CONCLUSIONS: These findings suggest that the newly isolated MI29 strain can activate host defense immunity and prevent infections caused by the influenza virus through the gut-lung axis. Video Abstract.

P. mirabilis-derived pore-forming haemolysin, HpmA drives intestinal alpha-synuclein aggregation in a mouse model of neurodegeneration.

BACKGROUND: Recent studies suggesting the importance of the gut-microbiome in intestinal aggregated alpha synuclein (α-syn) have led to the exploration of the possible role of the gut-brain axis in central nervous system degeneration. Proteus mirabilis (P. mirabilis), a gram-negative facultative anaerobic bacterium, has been linked to brain neurodegeneration in animal studies. We hypothesised that P. mirabilis-derived virulence factors aggregate intestinal α-synuclein and could prompt the pathogenesis of dopaminergic neurodegeneration in the brain. METHODS: We used vagotomised- and antibiotic-treated male murine models to determine the pathogenesis of P. mirabilis during brain neurodegeneration. The neurodegenerative factor that is driven by P. mirabilis was determined using genetically mutated P. mirabilis. The pathological functions and interactions of the virulence factors were determined in vitro. FINDINGS: The results showed that P. mirabilis-induced motor dysfunction and neurodegeneration are regulated by intestinal α-syn aggregation in vagotomised- or antibiotic-treated murine models. We deduced that the specific virulence factor, haemolysin A (HpmA), plays a role in the pathogenesis of P. mirabilis. HpmA is involved in α-synuclein oligomerisation and membrane pore formation, resulting in the activation of mTOR-mediated autophagy signalling in intestinal neuroendocrine cells. INTERPRETATION: Taken together, the results of the present study suggest that HpmA can interact with α-syn and act as a possible indicator of brain neurodegenerative diseases that are induced by P. mirabilis. FUNDING: This study was supported by a grant from the National Research Foundation of Korea.

Taurodeoxycholate ameliorates DSS-induced colitis in mice.

BACKGROUND: Inflammatory bowel disease (IBD) is typically managed using medications such as 5-aminosalicylic acid (5-ASA), glucocorticoids, anti-TNFα Ab, or anti-IL-12/23 Ab. However, some patients do not respond well to these treatments or frequently experience relapses. Therefore, alternative therapeutic options are needed. Since the activation of the inflammasome is crucial to the pathogenesis of IBD, inhibiting the inflammasome may be beneficial for patients. MATERIALS AND METHODS: We tested the efficacy of taurodeoxycholate (TDCA), which is a known G-protein coupled receptor 19 (GPCR19) agonist, in a mouse colitis model induced by dextran sodium sulfate (DSS). RESULTS: In the mouse colitis model, TDCA prevented loss of body weight, shortening of the colon, production of pro-inflammatory cytokines, infiltration of pro-inflammatory cells, and mucosal ulceration in the colon. In vitro, TDCA inhibited the activation of NF-κB in bone marrow-derived macrophages (BMDMs) by activating the cAMP-PKA axis. TDCA downregulated the expression of purinergic receptor P2X7 (P2X7R) and enhanced the colocalization of P2X7R with GPCR19, and inhibited the Ca2+ mobilization of BMDMs when stimulated with ATP or BzATP, which plays a pivotal role in activating the NLRP3 inflammasome (N3I) via P2X7R. TDCA inhibited the oligomerization of NLRP3-ASC and downregulated the expression of NLRP3 and ASC, as well as suppressed the maturation of pro-caspase-1 and pro-IL-1ß. TDCA also increased the percentage of M2 macrophages while decreasing the number of M1 macrophages, Th1, Th2, and Th17 cells in the colon. CONCLUSION: TDCA ameliorated DSS-induced colitis in mice, possibly by inhibiting both the priming phase (via the GPCR19-cAMP-PKA-NF-κB axis) and the activation phase (via the GPCR19-P2X7R-NLRP3-Caspase 1-IL-1ß axis) of N3I signaling.

CD115- monocytic myeloid-derived suppressor cells are precursors of OLFM4high polymorphonuclear myeloid-derived suppressor cells.

Myeloid-derived suppressor cells (MDSCs) consist of monocytic (M-) MDSCs and polymorphonuclear (PMN-) MDSCs that contribute to an immunosuppressive environment in tumor-bearing hosts. However, research on the phenotypic and functional heterogeneity of MDSCs in tumor-bearing hosts and across different disease stage is limited. Here we subdivide M-MDSCs based on CD115 expression and report that CD115- M-MDSCs are functionally distinct from CD115+ M-MDSCs. CD115- M-MDSCs increased in bone marrow and blood as tumors progressed. Transcriptome analysis revealed that CD115- M-MDSCs expressed higher levels of neutrophil-related genes. Moreover, isolated CD115- M-MDSCs had higher potential to be differentiated into PMN-MDSCs compared with CD115+ M-MDSCs. Of note, CD115- M-MDSCs were able to differentiate into both olfactomedin 4 (OLFM4)hi and OLFM4lo PMN-MDSCs, whereas CD115+ M-MDSCs differentiated into a smaller proportion of OLFM4lo PMN-MDSCs. In vivo, M-MDSC to PMN-MDSC differentiation occurred most frequently in bone marrow while M-MDSCs preferentially differentiated into tumor-associated macrophages in the tumor mass. Our study reveals the presence of previously unrecognized subtypes of CD115- M-MDSCs in tumor-bearing hosts and demonstrates their cellular plasticity during tumorigenesis.

Protective role of colitis in inflammatory arthritis via propionate-producing Bacteroides in the gut.

Objectives: To investigate whether and how inflammatory disease in the intestine influences the development of arthritis, considering that organ-to-organ communication is associated with many physiological and pathological events. Methods: First, mice were given drinking water containing dextran sodium sulfate (DSS) and then subjected to inflammatory arthritis. We compared the phenotypic symptoms between the cohoused and separately-housed mice. Next, donor mice were divided into DSS-treated and untreated groups and then cohoused with recipient mice. Arthritis was then induced in the recipients. The fecal microbiome was analyzed by 16S rRNA amplicon sequencing. We obtained type strains of the candidate bacteria and generated propionate-deficient mutant bacteria. Short-chain fatty acids were measured in the bacterial culture supernatant, serum, feces, and cecum contents using gas chromatography-mass spectrometry. Mice fed with candidate and mutant bacteria were subjected to inflammatory arthritis. Results: Contrary to expectations, the mice treated with DSS exhibited fewer symptoms of inflammatory arthritis. Intriguingly, the gut microbiota contributes, at least in part, to the improvement of colitis-mediated arthritis. Among the altered microorganisms, Bacteroides vulgatus and its higher taxonomic ranks were enriched in the DSS-treated mice. B. vulgatus, B. caccae, and B. thetaiotaomicron exerted anti-arthritic effects. Propionate production deficiency further prevented the protective effect of B. thetaiotaomicron on arthritis. Conclusions: We suggest a novel relationship between the gut and joints and an important role of the gut microbiota as communicators. Moreover, the propionate-producing Bacteroides species examined in this study may be a potential candidate for developing effective treatments for inflammatory arthritis.

Paraoxonase-2 contributes to promoting lipid metabolism and mitochondrial function via autophagy activation.

Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent immuno-metabolic disease that can progress to hepatic cirrhosis and cancer. NAFLD pathogenesis is extremely complex and is characterized by oxidative stress, impaired mitochondrial function and lipid metabolism, and cellular inflammation. Thus, in-depth research on its underlying mechanisms and subsequent investigation into a potential drug target that has overarching effects on these features will help in the discovery of effective treatments for NAFLD. Our study examines the role of endogenous paraoxonase-2 (PON2), a membrane protein with reported antioxidant activity, in an in vitro cell model of NAFLD. We found that the hepatic loss of PON2 activity aggravated steatosis and oxidative stress under lipotoxic conditions, and our transcriptome analysis revealed that the loss of PON2 disrupts the activation of numerous functional pathways closely related to NAFLD pathogenesis, including mitochondrial respiratory capacity, lipid metabolism, and hepatic fibrosis and inflammation. We found that PON2 promoted the activation of the autophagy pathway, specifically the mitophagy cargo sequestration, which could potentially aid PON2 in alleviating oxidative stress, mitochondrial dysfunction, lipid accumulation, and inflammation. These results provide a mechanistic foundation for the prospect of PON2 as a drug target, leading to the development of novel therapeutics for NAFLD.

AMPK suppresses Th2 cell responses by repressing mTORC2.

Allergic inflammation is a T helper 2 (Th2) cell-driven pathophysiological phenomenon, but the mechanism by which the metabolic cascade affects Th2 cell differentiation remains unclear. In this study, we investigated the roles of AMP-activated protein kinase (AMPK) and intracellular energy sensors in Th2 cell differentiation and the pathogenesis of allergic inflammation. Accordingly, T-cell-specific AMPK or Sirtuin 1 (Sirt1)-knockout mice were subjected to allergic inflammation, and their Th2 cell responses were investigated. The results demonstrated that inducing allergic inflammation in AMPK- and Sirt1-knockout mice increased Th2 cell responses and exacerbated allergic phenotypes. Furthermore, treatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMPK, ameliorated allergic inflammation in mice. Mechanistically, our findings revealed that AMPK repressed mechanistic target of rapamycin complex 2 (mTORC2), which downregulated the expression of suppressor of cytokine signaling 5 (SOCS5) in CD4+ T cells. In addition, the loss of AMPK signaling reduced SOCS5 expression and increased interleukin-4-STAT6-GATA3 axis-mediated Th2 cell differentiation. Finally, the T-cell-specific deletion of Rictor, a member of mTORC2, in Sirt1T-KO mice led to the reversal of allergic exacerbation to the level in control mice. Overall, our findings suggest that AMPK in CD4+ T cells inhibits the differentiation of Th2 cells by repressing mTORC2 and thus serves as a potential target for Th2 cell-associated diseases.

Emerging Japanese Encephalitis Virus Genotype V in Republic of Korea.

Japanese encephalitis (JE) is a vaccine-preventable mosquito-borne disease caused by infection with the Japanese encephalitis virus (JEV). JEV has five genotypes, including genotype V (GV), which is considered ancestral to the other genotypes. The first GV strain, GV Muar, was isolated from a Malayan patient in 1952 and GV did not reappear for 57 years until GV XZ0934 was isolated from a mosquito sample in China. Since 2010, 21 GV strains have been identified in Republic of Korea (ROK). Both GV Muar and GV XZ0934 are more pathogenic than other GI/GIII strains and are serologically distinct. However, because the ROK's GV strains have not been experimentally tested, their characteristics are not known. Characterization of the ROK's isolates is needed to enable development of effective GV strain-based vaccines to protect against GV infections.

Prospects on Repurposing a Live Attenuated Vaccine for the Control of Unrelated Infections.

Live vaccines use attenuated microbes to acquire immunity against pathogens in a safe way. As live attenuated vaccines (LAVs) still maintain infectivity, the vaccination stimulates diverse immune responses by mimicking natural infection. Induction of pathogen-specific antibodies or cell-mediated cytotoxicity provides means of specific protection, but LAV can also elicit unintended off-target effects, termed non-specific effects. Such mechanisms as short-lived genetic interference and non-specific innate immune response or long-lasting trained immunity and heterologous immunity allow LAVs to develop resistance to subsequent microbial infections. Based on their safety and potential for interference, LAVs may be considered as an alternative for immediate mitigation and control of unexpected pandemic outbreaks before pathogen-specific therapeutic and prophylactic measures are deployed.

High Level of SARS-CoV-2 Infection in Young Population Is a Predictor for Peak Incidence.

South Korea adopted stringent preventive measures against Coronavirus virus disease 2019, resulting in three small and one large outbreaks until January 15, 2022. The fatality rate was 2.5-fold higher during peak transmission periods than in base periods. As new variants of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) are continuously emerging, the need for understanding their epidemic potential remains necessary. In South Korea, the epidemiologic data obtained from mass diagnostic testing enabled investigation of the true number of infected cases, exact incidence, and fatality numbers. Analysis found a similarity between estimated infection rates and confirmed cases. This suggested that the number of confirmed cases had an influence on the fatality rate as a quantitative parameter. The fatality rate decreased even as infection with SARS-CoV-2 variants rose. In comparative analysis, the confirmed cases in young people (ages 20-29) increased prior to every outbreak peak and marked the tipping point in infection spread. These results indicate that a high level of SARS-CoV-2 infection in young population drives peak incidence and mortality across all age groups.

Nanoparticle and virus-like particle vaccine approaches against SARS-CoV-2.

The global spread of coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has provoked an urgent need for prophylactic measures. Several innovative vaccine platforms have been introduced and billions of vaccine doses have been administered worldwide. To enable the creation of safer and more effective vaccines, additional platforms are under development. These include the use of nanoparticle (NP) and virus-like particle (VLP) technology. NP vaccines utilize self-assembling scaffold structures designed to load the entire spike protein or receptor-binding domain of SARS-CoV-2 in a trimeric configuration. In contrast, VLP vaccines are genetically modified recombinant viruses that are considered safe, as they are generally replication-defective. Furthermore, VLPs have indigenous immunogenic potential due to their microbial origin. Importantly, NP and VLP vaccines have shown stronger immunogenicity with greater protection by mimicking the physicochemical characteristics of SARS-CoV-2. The study of NP- and VLP-based coronavirus vaccines will help ensure the development of rapid-response technology against SARS-CoV-2 variants and future coronavirus pandemics.

Bleomycin-Induced Lung Injury Increases Resistance to Influenza Virus Infection in a Type I Interferon-Dependent Manner.

Acute lung injury (ALI) results in acute respiratory disease that causes fatal respiratory diseases; however, little is known about the incidence of influenza infection in ALI. Using a ALI-mouse model, we investigated the pro-inflammatory cytokine response to ALI and influenza infection. Mice treated with bleomycin (BLM), which induces ALI, were more resistant to influenza virus infection and exhibited higher levels of type I interferon (IFN-I) transcription during the early infection period than that in PBS-treated control mice. BLM-treated mice also exhibited a lower viral burden, reduced pro-inflammatory cytokine production, and neutrophil levels. In contrast, BLM-treated IFN-I receptor 1 (IFNAR1)-knockout mice failed to show this attenuated phenotype, indicating that IFN-I is key to the antiviral response in ALI-induced mice. The STING/TBK1/IRF3 pathway was found to be involved in IFN-I production and the establishment of an antiviral environment in the lung. The depletion of plasmacytoid dendritic cells (pDCs) reduced the effect of BLM treatment against influenza virus infection, suggesting that pDCs are the major source of IFN-I and are crucial for defense against viral infection in BLM-induced lung injury. Overall, this study showed that BLM-mediated ALI in mice induced the release of double-stranded DNA, which in turn potentiated IFN-I-dependent pulmonary viral resistance by activating the STING/TBK1/IRF3 pathway in association with pDCs.

Microbiota-derived lactate promotes hematopoiesis and erythropoiesis by inducing stem cell factor production from leptin receptor+ niche cells.

Although functional interplay between intestinal microbiota and distant sites beyond the gut has been identified, the influence of microbiota-derived metabolites on hematopoietic stem cells (HSCs) remains unclear. This study investigated the role of microbiota-derived lactate in hematopoiesis using mice deficient in G-protein-coupled receptor (Gpr) 81 (Gpr81-/-), an established lactate receptor. We detected significant depletion of total HSCs in the bone marrow (BM) of Gpr81-/- mice compared with heterogenic (Gpr81+/-) mice in a steady state. Notably, the expression levels of stem cell factor (SCF), which is required for the proliferation of HSCs, decreased significantly in leptin receptor-expressing (LepR+) mesenchymal stromal cells (MSCs) around the sinusoidal vessels of the BM from Gpr81-/- mice compared with Gpr81+/- mice. Hematopoietic recovery and activation of BM niche cells after irradiation or busulfan treatment also required Gpr81 signals. Oral administration of lactic acid-producing bacteria (LAB) activated SCF secretion from LepR+ BM MSCs and subsequently accelerated hematopoiesis and erythropoiesis. Most importantly, LAB feeding accelerated the self-renewal of HSCs in germ-free mice. These results suggest that microbiota-derived lactate stimulates SCF secretion by LepR+ BM MSCs and subsequently activates hematopoiesis and erythropoiesis in a Gpr81-dependent manner.

RUVBL1/2 Complex Regulates Pro-Inflammatory Responses in Macrophages via Regulating Histone H3K4 Trimethylation.

Macrophages play an important role in the host defense mechanism. In response to infection, macrophages activate a genetic program of pro-inflammatory response to kill any invading pathogen, and initiate an adaptive immune response. We have identified RUVBL2 - an ATP-binding protein belonging to the AAA+ (ATPase associated with diverse cellular activities) superfamily of ATPases - as a novel regulator in pro-inflammatory response of macrophages. Gene knockdown of Ruvbl2, or pharmacological inhibition of RUVBL1/2 activity, compromises type-2 nitric oxide synthase (Nos2) gene expression, nitric oxide production and anti-bacterial activity of mouse macrophages in response to lipopolysaccharides (LPS). RUVBL1/2 inhibitor similarly inhibits pro-inflammatory response in human monocytes, suggesting functional conservation of RUVBL1/2 in humans. Transcriptome analysis further revealed that major LPS-induced pro-inflammatory pathways in macrophages are regulated in a RUVBL1/2-dependent manner. Furthermore, RUVBL1/2 inhibition significantly reduced the level of histone H3K4me3 at the promoter region of Nos2 and Il6, two prototypical pro-inflammatory genes, and diminished the recruitment of NF-kappaB to the corresponding enhancers. Our study reveals RUVBL1/2 as an integral component of macrophage pro-inflammatory responses through epigenetic regulations, and the therapeutic potentials of RUVBL1/2 inhibitors in the treatment of diseases caused by aberrant activation of pro-inflammatory pathways.

RNA-dependent assembly of chimeric antigen nanoparticles as an efficient H5N1 pre-pandemic vaccine platform.

Highly pathogenic avian influenza viruses (HPAIVs) pose a significant threat to human health, with high mortality rates, and require effective vaccines. We showed that, harnessed with novel RNA-mediated chaperone function, hemagglutinin (HA) of H5N1 HPAIV could be displayed as an immunologically relevant conformation on self-assembled chimeric nanoparticles (cNP). A tri-partite monomeric antigen was designed including: i) an RNA-interaction domain (RID) as a docking tag for RNA to enable chaperna function (chaperna: chaperone + RNA), ii) globular head domain (gd) of HA as a target antigen, and iii) ferritin as a scaffold for 24 mer-assembly. The immunization of mice with the nanoparticles (~46 nm) induced a 25-30 fold higher neutralizing capacity of the antibody and provided cross-protection from homologous and heterologous lethal challenges. This study suggests that cNP assembly is conducive to eliciting antibodies against the conserved region in HA, providing potent and broad protective efficacy.

Detection of Salmonella genes in stool samples of children aged 5 years and younger in urban and rural areas of Bangladesh.

INTRODUCTION: Typhoid incidence in children is higher in urban areas than in rural areas of Bangladesh. This study examined whether healthy urban children harboured higher levels of Salmonella genes than healthy rural children. METHODOLOGY: Stool samples from 140 children were studied: 70 from rural areas and 70 from urban metropolitan areas. RESULTS: The stool samples of urban children contained more Salmonella genes (median 4, IQR 3-4) than those of rural children (median 3, IQR 3-4). This suggests that urban Bangladeshi children have more Salmonella genes in their guts than rural children. Especially, in those under 12 months of age, the Salmonella gene prevalence in urban children was unique. They had more Salmonella genes (median 4, IQR 4-5) than rural children in the same age group (median 3, IQR 2.5-4). We also found more Salmonella genes in urban children who drank tap water (median 4, IQR 3-5) than in rural children whose water source was tube well water (median 3, IQR 2-4) and boiled pond water (median 3, IQR 3-3.5). However, there was no significant difference of Salmonella genes between urban children who drank tap-water and children whose water source was a tube well (median 4, IQR 3-4). CONCLUSIONS: These data suggest that the urban environment, including the drinking water supply system, increases the likelihood of healthy children in urban areas harbouring more potentially pathogenic Salmonella organisms in their gut than found in rural healthy children.

Geranylgeranyl pyrophosphate amplifies Treg differentiation via increased IL-2 expression to ameliorate DSS-induced colitis.

Blocking the mevalonate pathway for cholesterol reduction by using statin may have adverse effects including statin-induced colitis. Moreover, one of the predisposing factors for colitis is an imbalanced CD4+ T cell, which can be observed on the complete deletion of HMG-CoA reductase (HMGCR), a target of statins. In this study, we inquired geranylgeranyl pyrophosphate (GGPP) is responsible for maintaining the T-cell homeostasis. Following dextran sulfate sodium (DSS)-induced colitis, simvastatin increased the severity of disease, while cotreatment with GGPP, but not with cholesterol, reversed the disease magnitude. GGPP ameliorated DSS-induced colitis by increasing Treg cells. GGPP amplified Treg differentiation through increased IL-2/STAT 5 signaling. GGPP prenylated Ras protein, a prerequisite for extracellular signal-regulated kinase (ERK) pathway activation, leading to increased IL-2 production. Higher simvastatin dose increased the severity of colitis. GGPP ameliorated simvastatin-increased colitis by increasing Treg cells. Treg cells, which have the capacity to suppress inflammatory T cells and were generated through IL-2/STAT5 signaling, increased IL-2 production through prenylation and activation of the Ras/ERK pathway.

Endogenous DEL-1 restrains melanoma lung metastasis by limiting myeloid cell-associated lung inflammation.

Distant metastasis represents the primary cause of cancer-associated death. Pulmonary metastasis is most frequently seen in many cancers, largely driven by lung inflammation. Components from primary tumor or recruited leukocytes are known to facilitate metastasis formation. However, contribution of target site-specific host factor to metastasis is poorly understood. Here, we show that developmental endothelial locus-1 (DEL-1), an anti-inflammatory factor abundant in the lung and down-regulated by inflammatory insults, protects from melanoma lung metastasis independently of primary tumor development and systemic immunosurveillance. DEL-1 deficiency is associated with gene profiles that favor metastatic progression with inflammation and defective immunosurveillance. Mechanistically, DEL-1 deficiency primarily influences Ly6G+ neutrophil accumulation in lung metastatic niche, leading to IL-17A up-regulation from γδ T cells and reduced antimetastatic NK cells. In support, neutrophil depletion or recombinant DEL-1 treatment profoundly reverses these effects. Thus, our results identify DEL-1 as a previously unrecognized link between tumor-induced inflammation and pulmonary metastasis.