ANKRD22 promotes resolution of psoriasiform skin inflammation by antagonizing NIK-mediated IL-23 production.

Inflammation resolution is an essential process for preventing the development of chronic inflammatory diseases. However, the mechanisms that regulate inflammation resolution in psoriasis are not well understood. Here, we report that ANKRD22 is an endogenous negative orchestrator of psoriasiform inflammation because ANKRD22-deficient mice are more susceptible to IMQ-induced psoriasiform inflammation. Mechanistically, ANKRD22 deficiency leads to excessive activation of the TNFRII-NIK-mediated noncanonical NF-κB signaling pathway, resulting in the hyperproduction of IL-23 in DCs. This is due to ANKRD22 being a negative feedback regulator for NIK because it physically binds to and assists in the degradation of accumulated NIK. Clinically, ANKRD22 is negatively associated with IL-23A expression and psoriasis severity. Of greater significance, subcutaneous administration of an AAV carrying ANKRD22-overexpression vector effectively hastens the resolution of psoriasiform skin inflammation. Our findings suggest ANKRD22, an endogenous supervisor of NIK, is responsible for inflammation resolution in psoriasis, and may be explored in the context of psoriasis therapy.

A vaccine delivery system promotes strong immune responses against SARS-CoV-2 variants.

Global coronavirus disease 2019 (COVID-19) pandemics highlight the need of developing vaccines with universal and durable protection against emerging SARS-CoV-2 variants. Here we developed an extended-release vaccine delivery system (GP-diABZI-RBD), consisting the original SARS-CoV-2 WA1 strain receptor-binding domain (RBD) as the antigen and diABZI stimulator of interferon genes (STING) agonist in conjunction with yeast ß-glucan particles (GP-diABZI) as the platform. GP-diABZI-RBD could activate STING pathway and inhibit SARS-CoV-2 replication. Compared to diABZI-RBD, intraperitoneal injection of GP-diABZI-RBD elicited robust cellular and humoral immune responses in mice. Using SARS-CoV-2 GFP/ΔN transcription and replication-competent virus-like particle system (trVLP), we demonstrated that GP-diABZI-RBD-prototype vaccine exhibited the strongest and durable humoral immune responses and antiviral protection; whereas GP-diABZI-RBD-Omicron displayed minimum neutralization responses against trVLP. By using pseudotype virus (PsVs) neutralization assay, we found that GP-diABZI-RBD-Prototype, GP-diABZI-RBD-Delta, and GP-diABZI-RBD-Gamma immunized mice sera could efficiently neutralize Delta and Gamma PsVs, but had weak protection against Omicron PsVs. In contrast, GP-diABZI-RBD-Omicron immunized mice sera displayed the strongest neutralization response to Omicron PsVs. Taken together, the results suggest that GP-diABZI can serve as a promising vaccine delivery system for enhancing durable humoral and cellular immunity against broad SARS-CoV-2 variants. Our study provides important scientific basis for developing SARS-CoV-2 VOC-specific vaccines.

Prognosis of the Keratinizing Squamous Cell Carcinoma of the Tongue Based on Surveillance, Epidemiology, and End Results Database.

Background: The objective of this study is to determine the prognostic factors of keratinizing squamous cell carcinoma of the tongue (KTSCC) and to establish a prognostic nomogram of KTSCC to assist clinical diagnosis and treatment. Methods: This study identified 3874 patients with KTSCC from the Surveillance, Epidemiology, and End Results (SEER) database, and these patients were randomly divided into the training (70%, (n = 2711) and validation (30%, n = 1163) cohorts. Cox regression was then used to filter variables. Nomograms were then constructed based on meaningful variables. Finally, the concordance index (C-index), net reclassification index (NRI), integrated discrimination improvement (IDI), calibration charts, and decision-curve analysis (DCA), were used to evaluate the discrimination, accuracy and effectiveness of the model. Results: A nomogram model was established for predicting the 3-, 5-, and 8-year overall survival (OS) probabilities of patients with KTSCC. The model indicated that age, radiotherapy sequence, SEER stage, marital status, tumor size, American Joint Committee on Cancer (AJCC) stage, radiotherapy status, race, lymph node dissection status, and sex were factors influencing the OS of patients with KTSCC. Verified by C-index, NRI, IDI, calibration curve, and DCA curve, our model has better discrimination, calibration, accuracy and net benefit compared to the AJCC system. Conclusions: This study identified the factors that affect the survival of KTSCC patients and established a prognostic nomogram that can help clinicians predict the 3-, 5-, and 8-year survival rates of KTSCC patients.

Antiapoptotic properties of MALT1 protease are associated with redox homeostasis in ABC-DLBCL cells.

Mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) protease presents crucial antiapoptotic properties in activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL); however, the mechanism is unclear. Here, we reported that inhibition of MALT1 protease in ABC-DLBCL cells led to cell apoptosis, along with elevated mitochondrial reactive oxygen species production and a reduced oxygen consumption rate. These alterations induced by MALT1 protease inhibition were associated with reduced expression of glutaminase (GLS1) and glutathione levels. We further show that MALT1 protease was required for the activation and nuclear translocation of c-Jun, which functions as a transcription factor of the GLS1 gene by binding directly to its promoter region. Taken together, MALT1 protease maintained mitochondrial redox homeostasis and mitochondrial bioenergetics through the MALT1-c-Jun-GLS1-coupled metabolic pathway to defend against apoptosis in ABC-DLBCL cells, which raises exciting possibilities regarding targeting of the MALT1-c-Jun-GLS1 axis as a potential therapeutic strategy against ABC-DLBCL.

Oncogenic activin C interacts with decorin in colorectal cancer in vivo and in vitro.

Activin C is a member of the transforming growth factor-ß (TGF-ß) superfamily with various biological activities. Decorin is a member of the small leucine-rich proteoglycan family, which can bind to TGF-ß and modulate TGF-ß-mediated signaling. In the decorin-deficient mouse model, we found that the expression of activin C was remarkably increased in the intestine of Dcn-/- mice compared to the expression of activin C in the intestine of Dcn+/+ mice. Addition of activin C protein to colorectal cancer cells or over-expression of activin C in these cells stimulated cell growth, migration, and invasion in vitro. Enhanced AP-1 expression in colorectal cancer cells was found to be associated with the oncoprotein-like effects of activin C through the JNK/AP-1 pathway, and not the Smad signaling pathway. However, these effects were abolished when decorin expression was restored by transfecting the cells with a decorin-expressing plasmid or by reducing the expression of activin C via interfering RNA. Further analysis demonstrated that decorin could directly bind to and accelerate the degradation of activin C. In conclusion, our data provided the first evidence demonstrating the oncogenic role of activin C in intestinal tumorigenesis of decorin-deficient mice and colorectal cancer cells. © 2015 Wiley Periodicals, Inc.

Protein tyrosine phosphatase 1B inhibitory effect by dammarane-type triterpenes from hydrolyzate of total Gynostemma pentaphyllum saponins.

Protein tyrosine phosphatase 1B (PTP1B) is an important factor in non-insulin-dependent diabetes mellitus (type-2 diabetes), and a promising target for treatment of diabetes and obesity. Therefore, the aim of this study is to investigate the inhibitory activities of constituents (three new together with twelve known triterpenes compounds) isolated from the hydrolyzate of total saponins from Gynostemma pentaphyllum. Their structures were accomplished mainly base on the spectroscopic methods, and then were further confirmed by X-ray crystal diffraction. All the compounds were evaluated for inhibitory activity against PTP1B. Current data suggested that the compounds 1, 3, 12, 13 and 14 were considered to be potential as antidiabetic agents, in which they could significantly inhibit the PTP1B enzyme activity in a dose-dependent manner.

Inhibition of ß-catenin signaling involved in the biological activities of a lignan E2S isolated from Carya cathayensis fruits.

Carya cathayensis is a fruit-bearing plant that belongs to the Juglandaceae family and is widely distributed throughout the world. It possesses various important biological activities. We have previously isolated an antitumor compound from the shell of C. cathayensis fruits and named it E2S ((E)-3-[(2S,3R)-2,3-dihydro-2-(4'-hydroxy-3'-methoxyphenyl)-3-hydroxymethyl-7-methoxy-1-benzo[b]furan-5-yl]-2-propenal). In this study, we investigated the antitumor activity of E2S against various human colorectal cancer cell lines (HCT116, HT29, SW480, LoVo). The results showed that E2S could significantly inhibit the growth of cancer cells in a dose-dependent manner, as well as disrupt the progression of the cell cycle. Mechanistic study revealed that E2S could decrease the protein levels of ß-catenin and its downstream targets (such as c-myc, a key transcriptional target of ß-catenin) in the cells. In addition, it also significantly suppressed ß-catenin/TCF transcriptional activity. Taken together, the results suggested that E2S might partially exert an antiproliferative effect on human colorectal cancer cells by targeting ß-catenin signaling, a finding that might potentially translate into a chemotherapeutic strategy for the treatment of cancer. It might also have implications for cancer prevention strategies.

Transcriptome Analysis Identifies Biomarkers for the Diagnosis and Management of Psoriasis Complicated with Depression.

Purpose: Psoriasis is a systemic inflammatory disease, and the mechanism that links psoriasis to depression is still elusive. Hence, this study aimed to elucidate the potential pathogenesis of psoriasis and depression comorbidity. Methods: The gene expression profiles of psoriasis (GSE34248, GSE78097 and GSE161683) and depression (GSE39653) were downloaded from the Gene Expression Omnibus (GEO) DataSets. Functional annotation, protein-protein interaction (PPI) network and module construction, and hub gene identification and co-expression analysis were performed, following identification of the common differentially expressed genes (DEGs) of psoriasis and depression. Results: A total of 115 common DEGs (55 up-regulated and 60 down-regulated) were identified between psoriasis and depression. Functional analysis indicated that T cell activation and differentiation were predominantly implicated in the potential pathogenesis of these two diseases. In addition, Th17 cell differentiation and cytokines is closely related to both. Finally, 17 hub genes were screened, including CTLA4, LCK, ITK, IL7R, CD3D, SOCS1, IL4R, PRKCQ, SOCS3, IL23A, PDGFB, PAG1, TGFA, FGFR1, RELN, ITGB5 and TNXB, which re-emphasized the importance of the immune system in psoriasis and depression. Conclusion: Our study reveals the common pathogenesis of psoriasis and depression. These common pathways and hub genes may apply to a molecular screening tool for depression in psoriasis patients, which could help dermatologists optimize patient management in routine care.

Liquiritin apioside alleviates colonic inflammation and accompanying depression-like symptoms in colitis by gut metabolites and the balance of Th17/Treg.

BACKGROUND: Inflammatory bowel disease (IBD) is a significant global health concern that can lead to depression in affected patients. Liquiritin apioside (LA) possesses anti-oxidative and anti-inflammatory properties. However, its anti-inflammatory mechanism in IBD has not been extensively studied. PURPOSE: This study elucidates the pivotal role of LA in alleviating inflammation by regulating gut metabiota-derived metabolites and evaluating its regulative effects on promoting a balance of Th17/Treg cells in colitis mice. METHODS: To evaluate the effect of LA on IBD,16S rRNA gene sequencing and UPLC-QTOF-MS analysis were used to identify the changes of intestinal bacteria and their metabolites. Cytokines levels were determined by ELISA and qPCR, while immune cell ratios were evaluated via flow cytometry. RESULTS: Our findings revealed that LA treatment ameliorated general states of DSS-induced colitis mice and their accompanying depressive behaviors. Moreover, LA restricted the expression of pro-inflammatory cytokines and revised the imbalanced Treg/Th17 differentiation, while promoting SCFAs production in inflamed colon tissues. Fecal microbiota transplantation from LA-fed mice also corrected the imbalanced Treg/Th17 differentiation, indicating that LA-mediated restoration of the colonic Treg/Th17 balance mainly depends on the changes in gut metabolites. CONCLUSION: These results provide scientific evidence explaining the apparent paradox of low bioavailability and high bioactivity in polyphenols, and suggesting that LA could be used as a potential dietary supplement for the prevention and improvement of IBD.

RNA-Seq and ATAC-Seq analyses reveal a global transcriptional and chromatin accessibility profiling of γδ T17 differentiation from mouse spleen.

IL-17A-producing γδ T cells (γδ T17) are known to play important roles in various autoimmune diseases. However, the molecular mechanisms of γδ T17 differentiation and their functions have not been clarified yet. Here, we sorted IL-17A+ Vγ4, IL-17A- Vγ4, and Vγ1 subsets from mouse spleen by in vitro priming of γδ T17 cells and investigated their differentially expressed genes (DEGs) and differentially accessible regions (DARs) using RNA-seq and ATAC-seq, respectively. Our results showed that DEGs-1 (upregulated genes: 677 and downregulated genes: 821) and DEGs-2 (upregulated genes: 1188 and downregulated genes: 1252) were most closely related to the function and differentiation of peripheral γδ T17. We identified key modules and MCODEs involved in the control of IL-17A+ Vγ4, IL-17A- Vγ4, and Vγ1 subsets using the WGCNA and Metascape analysis. Furthermore, 26 key transcription factors were enriched in three subsets, which contributed to deciphering the potential molecular mechanism driving γδ T17 differentiation. Simultaneously, we conducted chromatin accessibility profiling under γδ T17 differentiation by ATAC-seq. The top six candidate genes were screened for γδ T17 differentiation and function by integrating RNA-seq and ATAC-seq analysis, and the results were further confirmed using RT-qPCR, flow cytometry, and western blot. In addition, the association analysis of candidate genes with the RNA-seq database of psoriasis was performed to elucidate the functional relationship. Our findings provided a novel insight into understanding the molecular mechanisms of γδ T17 differentiation and function and may improve to the development of therapeutic approaches or drugs targeting γδ T17 for autoimmune diseases.

Deep-learning-based survival prediction of patients with cutaneous malignant melanoma.

Background: This study obtained data on patients with cutaneous malignant melanoma (CMM) from the Surveillance, Epidemiology, and End Results (SEER) database, and used a deep learning and neural network (DeepSurv) model to predict the survival rate of patients with CMM and evaluate its effectiveness. Methods: We collected information on patients with CMM between 2004 and 2015 from the SEER database. We then randomly divided the patients into training and testing cohorts at a 7:3 ratio. The likelihood that patients with CMM will survive was forecasted using the DeepSurv model, and its results were compared with those of the Cox proportional-hazards (CoxPH) model. The calibration curves, time-dependent area under the receiver operating characteristic curve (AUC), and concordance index (C-index) were used to assess the prediction abilities of the model. Results: This study comprised 37,758 patients with CMM: 26,430 in the training cohort and 11,329 in the testing cohort. The CoxPH model demonstrated that the survival of patients with CMM was significantly influenced by age, sex, marital status, summary stage, surgery, radiotherapy, chemotherapy, postoperative lymph node dissection, tumor size, and tumor extension. The C-index of the CoxPH model was 0.875. We also constructed the DeepSurv model using the data from the training cohort, and its C-index was 0.910. We examined how well the aforementioned two models predicted outcomes. The 1-, 3-, and 5-year AUCs were 0.928, 0.837, and 0.855, respectively, for the CoxPH model, and 0.971, 0.947, and 0.942 for the DeepSurv model. The DeepSurv model presented a greater predictive effect on patients with CMM, and its reliability was better than that of the CoxPH model according to both the AUC value and the calibration curve. Conclusion: The DeepSurv model, which we developed based on the data of patients with CMM in the SEER database, was found to be more effective than the CoxPH model in predicting the survival time of patients with CMM.

SLC38A5 aggravates DC-mediated psoriasiform skin inflammation via potentiating lysosomal acidification.

Amino acid (aa) metabolism is closely correlated with the pathogenesis of psoriasis; however, details on aa transportation during this process are barely known. Here, we find that SLC38A5, a sodium-dependent neutral aa transporter that counter-transports protons, is markedly upregulated in the psoriatic skin of both human patients and mouse models. SLC38A5 deficiency significantly ameliorates the pathogenesis of psoriasis, indicating a pathogenic role of SLC38A5. Surprisingly, SLC38A5 is almost exclusively expressed in dendritic cells (DCs) when analyzing the psoriatic lesion and mainly locates on the lysosome. Mechanistically, SLC38A5 potentiates lysosomal acidification, which dictates the cleavage and activation of TLR7 with ensuing production of pro-inflammatory cytokines such as interleukin-23 (IL-23) and IL-1ß from DCs and eventually aggravates psoriatic inflammation. In summary, this work uncovers an auxiliary mechanism in driving lysosomal acidification, provides inspiring insights for DC biology and psoriasis etiology, and reveals SLC38A5 as a promising therapeutic target for treating psoriasis.

1α,25(OH)2D3 reverses exhaustion and enhances antitumor immunity of human cytotoxic T cells.

BACKGROUND: Epidemiological surveys have revealed that low serum vitamin D level was correlated with increased risk of tumors. Dysfunctional T cells in patients with tumor are characterized as exhausted with high levels of immune checkpoint receptors (ICRs). However, whether the reduced level of vitamin D in patients with cancer correlates with cytotoxic T-cell exhaustion is unknown. METHODS: Periphery blood samples from 172 patients with non-small cell lung cancer (NSCLC) were prospectively collected. Patients with NSCLC received one course of intravenous docetaxel (75 mg/m2) followed by treatment with or without rocaltrol at a dose of 0.5-2.0 µg/day for total of 3 weeks. We performed phenotypical and functional analysis of T-cell through flow cytometry. Vitamin D receptor (VDR) knockout and overexpression CD8+ and Vδ2+ T cells were constructed using Cas9-gRNA targeted and overexpressing approaches to identify 1α,25(OH)2D3/VDR-mediated transcription regulation for ICRs or antitumor activity in T cells. RESULTS: We show that serum level of vitamin D is negatively correlated with expression of programmed cell death-1 (PD-1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), but positively correlated with CD28 expression on CD8+ and Vγ9Vδ2+ T cells in patients with NSCLC. 1α,25(OH)2D3, the active form of vitamin D, promotes the nuclear translocation of VDR, which binds to the promoter region of Pdcd1, Tim3, and Tigit genes and inhibits their expression. Besides, 1α,25(OH)2D3 pretreatment also promotes the methylation of CpG island in the promoter region of the Pdcd1 gene and increases H3K27 acetylation at the promoter region of the Cd28 gene, which leads to surface PD-1 downregulation and CD28 upregulation, respectively. We further reveal that VDR-mediated Ca2+ influx enhanced expression of Th1 cytokines via T-cell receptor activation. Functionally, 1α,25(OH)2D3 pretreated CD8+ T cells or Vγ9Vδ2+ T cells showed increased Th1 cytokine production and enhanced antitumor immunity. Finally, oral 1α,25(OH)2D3 could also decrease expression of PD-1, Tim-3, TIGIT and increase expression of CD28, resulting in cytokine production (associated with antitumor immunity) by cytotoxic T cells of patients with NSCLC. CONCLUSIONS: Our findings uncover the pleiotropic effects of 1α,25(OH)2D3 in rescuing the exhausted phenotype of human cytotoxic T cells in patients with tumor and in promoting their antitumor immunity. TRIAL REGISTRATION NUMBER: ChiCTR2100051135.

PPP1R14B Is a Prognostic and Immunological Biomarker in Pan-Cancer.

Recent studies have shown that PPP1R14B was highly expressed in tumor tissues and patients with high expression of PPP1R14B had poor survival rates. However, the function and mechanisms of PPP1R14B in tumor progression remain ill defined. There was also lack of pan-cancer evidence for the relationship between PPP1R14B and various tumor types based on abundant clinical data. We used the TCGA project and GEO databases to perform pan-cancer analysis of PPP1R14B, including expression differences, correlations between expression levels and survival, genetic alteration, immune infiltration, and relevant cellular pathways, to investigate the functions and potential mechanisms of PPP1R14B in the pathogenesis or clinical prognosis of different cancers. Herein, we found that PPP1R14B was involved in the prognosis of pan-cancer and closely related to immune infiltration. Increased PPP1R14B expression correlated with poor prognosis and increased immune infiltration levels in myeloid-derived suppressor cells (MDSCs). Our studies suggest that PPP1R14B can be used as a prognostic biomarker for pan-cancer. Our findings may provide an antitumor strategy targeting PPP1R14B, including manipulation of tumor cell growth or the tumor microenvironment, especially myeloid-derived suppressor cell infiltration.

Yeast Shells Encapsulating Adjuvant AS04 as an Antigen Delivery System for a Novel Vaccine against Toxoplasma Gondii.

Toxoplasma gondii (T. gondii) infection causes severe zoonotic toxoplasmosis, which threatens the safety of almost one-third of the human population globally. However, there is no effective protective vaccine against human toxoplasmosis. This necessitates anti-T. gondii vaccine development, which is a main priority of public health. In this study, we optimized the adjuvant system 04 (AS04), a vaccine adjuvant constituted by 3-O-desacyl-4'-monophosphoryl lipid A (a TLR4 agonist) and aluminum salts, by packing it within natural extracts of ß-glucan particles (GPs) from Saccharomyces cerevisiae to form a GP-AS04 hybrid adjuvant system. Through a simple mixing procedure, we loaded GP-AS04 particles with the total extract (TE) of T. gondii lysate, forming a novel anti-T. gondii vaccine GP-AS04-TE. Results indicated that the hybrid adjuvant can efficiently and stably load antigens, mediate antigen delivery, facilitate the dendritic uptake of antigens, boost dendritic cell maturation and stimulation, and increase the secretion of pro-inflammatory cytokines. In the mouse inoculation model, GP-AS04-TE significantly stimulated the function of dendritic cells, induced a very strong TE-specific humoral and cellular immune response, and finally showed a strong and effective protection against toxoplasma chronic and acute infections. This work proves the potential of GP-AS04 for exploitation as a vaccine against a range of pathogens.

GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis.

Psoriasis is a severe disease associated with the disturbance of metabolism and inflammation, but the molecular mechanisms underlying these aspects of psoriasis pathology are poorly understood. Here, we report that glutaminase 1-mediated (GLS1-mediated) glutaminolysis was aberrantly activated in patients with psoriasis and in psoriasis-like mouse models, which promoted Th17 and γδ T17 (IL-17A-producing γδ T) cell differentiation through enhancement of histone H3 acetylation of the Il17a promoter, thereby contributing to the immune imbalance and development of psoriasis. We further demonstrate that mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) protease was constitutively active in psoriatic CD4+ and γδ T cells, thereby supporting GLS1 expression by stabilizing c-Jun, which directly binds to the GLS1 promoter region. Blocking the activity of either GLS1 or MALT1 protease resolved Th17 and γδ T17 cell differentiation and epidermal hyperplasia in the psoriasis-like mouse models. Finally, IL-17A enhanced GLS1 expression via the MALT1/cJun pathway in keratinocytes, resulting in hyperproliferation of and chemokine production by keratinocytes. Our findings identify the role of the MALT1/cJun/GLS1/glutaminolysis/H3 acetylation/T17 axis in psoriasis pathogenesis and reveal potential therapeutic targets for this disease.

Feruloylated Oligosaccharides Alleviate Dextran Sulfate Sodium-Induced Colitis in Vivo.

The imbalance of T lymphocyte subsets substantially conduces to disturbed intestinal immune system and succeeding colonic tissue damage in inflammatory bowel diseases. It is considered that regulation of phytochemicals on cytokine production potentially provides a broad prospect for the exploitation of immunomodulatory agents. Here, we reported that oral administration of feruloylated oligosaccharides (FOs) effectively alleviated mice colitis disease induced by dextran sulfate sodium (DSS). FOs decreased the percentage of T helper (Th)17 cells and downregulated the production of Th17-specific cytokines. In contrast, FOs increased the percentage of regulatory T (Treg) cells and elevated the production of Treg-specific cytokines in colons of DSS-challenged mice. These results indicated that FOs restored the immunologic equilibrium of Th17 and Treg subsets, hereby ameliorating the deterioration of colitis. Furthermore, FOs diminished the secretion of interleukin (IL)-23 and IL-6 but enhanced the transforming growth factor-ß1 (TGF-ß1) in dendritic cells in vitro and in vivo, which contributed to the restoration of Th17 and Treg cells immune balance. The mechanistic analysis showed that the regulation of FOs on IL-23 and IL-6 was associated with the nuclear factor-κ-gene binding signaling pathway and TGF-ß1 with mitogen-activated protein kinase-activator protein 1 signaling pathway. Taken together, oral administration of FOs exerted potent immunomodulatory effects against mice colitis via restoring the immune balance of Th17 and Treg cells.

Inhibition of MALT1 paracaspase activity improves lesion recovery following spinal cord injury.

Spinal cord injury (SCI) is a devastating traumatic injury that causes persistent, severe motor and sensory dysfunction. Immune responses are involved in functional recovery after SCI. Mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) has been shown to regulate the survival and differentiation of immune cells and to play a critical role in many diseases, but its function in lesion recovery after SCI remains unclear. In this paper, we generated KI (knock in) mice with a point mutation (C472G) in the active center of MALT1 and found that the KI mice exhibited improved functional recovery after SCI. Fewer macrophages were recruited to the injury site in KI mice and these macrophages differentiated into anti-inflammatory macrophages. Moreover, macrophages from KI mice exhibited reduced phosphorylation of p65, which in turn resulted in decreased SOCS3 expression and increased pSTAT6 levels. Similar results were obtained upon inhibition of MALT1 paracaspase with the small molecule inhibitor "MI-2" or the more specific inhibitor "MLT-827". In patients with SCI, peripheral blood mononuclear cells (PBMC) displayed increased MALT1 paracaspase. Human macrophages showed reduced pro-inflammatory and increased anti-inflammatory characteristics following the inhibition of MALT1 paracaspase. These findings suggest that inhibition of MALT1 paracaspase activity in the clinic may improve lesion recovery in subjects with SCI.

Glutaminolysis Mediated by MALT1 Protease Activity Facilitates PD-L1 Expression on ABC-DLBCL Cells and Contributes to Their Immune Evasion.

Previous studies have demonstrated that programmed death-1 ligand 1 (PD-L1) expressed in an aggressive activated B-cell (ABC)/non-germinal center B cell-like (GCB) subtype of diffuse large B-cell lymphoma (DLBCL) is associated with inhibition of the tumor-associated T cell response. However, the molecular mechanism underlying PD-L1 expression in ABC-DLBCL remains unclear. Here, we report that MALT1 protease activity is required for ABC-DLBCL cells to evade cytotoxity of Vγ9Vδ2 T lymphocytes by generating substantial PD-L1+ ABC-DLBCL cells. While, NF-κB was dispensable for the PD-L1 expression induced by MALT1 protease activity in ABC-DLBCL cells. Furthermore, we showed that GLS1 expression was profoundly reduced by MALT1 protease activity inhibition, which resulted in insufficiency of glutaminolysis-derived mitochondrial bioenergetics. Activation of the PD-L1 transcription factor STAT3, which was strongly suppressed by glutaminolysis blockade, was rescued in a TCA (tricarboxylic acid) cycle-dependent manner by glutamate addition. Collectively, MALT1 protease activity coupled with glutaminolysis-derived mitochondrial bioenergetics plays an essential role in PD-L1 expression on ABC-DLBCL cells under immunosurveillance stress. Thus, our research sheds light on a mechanism underlying PD-L1 expression and highlights a potential therapeutic target to vanquish immune evasion by ABC-DLBCL cells.

c-Jun NH2-teminal kinase 1 interacts with vitamin D receptor and affects vitamin D-mediated inhibition of cancer cell proliferation.

BACKGROUND: Vitamin D is a chemopreventive agent that acts against colorectal carcinogenesis in vivo and in vitro through vitamin D receptor (VDR). Previous studies showed that stress-activated protein kinase JNKs (c-Jun NH2-terminal kinases) and p38 cooperated to activate VDR and increase vitamin D3-dependent growth inhibition in breast cancer cells. This study is to determine whether vitamin D-mediated inhibition of cell proliferation is associated with JNK1 in colorectal cancer cells. METHODS AND RESULTS: Human colon cancer cells were treated with calcitriol, an active vitamin D3. The results showed that calcitriol significantly inhibited cell proliferation and caused cell cycle arrest in HT29 cells, which was associated with induction of phosphorylated JNK1 (p-JNK). The induction of VDR and p-JNK by calcitriol was also observed in Caco-2 cells. Furthermore, VDR expression was significantly downregulated in JNK1-/- mouse intestinal epithelial cells, and VDR reporter activity was reduced in JNK1-/- mouse embryonic fibroblasts (MEFs). However, increasing activated JNK1 upregulated VDR expression and transcriptional activity in vitro. Moreover, JNK1 co-localized with VDR in nuclei and cytoplasm and physically bound together. Reduced expression of JNK1 and VDR in HT29 and Caco-2 cells and JNK1 absence in JNK1-/- MEFs attenuated calcitriol-mediated inhibition of cell proliferation. CONCLUSION: JNK1 physically and functionally interacted with VDR and positively regulated VDR expression at transcriptional and translational levels, which influenced calcitriol-mediated inhibition of cancer cell proliferation.