ABSTRACT
Excessive host immune responses contribute to severe malaria with high mortality. Here, we show that PRL2 in innate immune cells is highly related to experimental malaria disease progression, especially the development of murine severe malaria. In the absence of PRL2 in myeloid cells, Plasmodium berghei infection results in augmented lung injury, leading to significantly increased mortality. Intravital imaging revealed greater neutrophilic inflammation and NET formation in the lungs of PRL2 myeloid conditional knockout mice. Depletion of neutrophils prior to the onset of severe disease protected mice from NETs associated lung injury, and eliminated the difference between WT and PRL2 CKO mice. PRL2 regulates neutrophil activation and NET accumulation via the Rac-ROS pathway, thus contributing to NETs associated ALI. Hydroxychloroquine, an inhibitor of PRL2 degradation alleviates NETs associated tissue damage in vivo. Our findings suggest that PRL2 serves as an indicator of progression to severe malaria and ALI. In addition, our study indicated the importance of PRL2 in NET formation and tissue injury. It might open a promising path for adjunctive treatment of NET-associated disease.
Subject(s)
Acute Lung Injury , Extracellular Traps , Immediate-Early Proteins , Malaria , Protein Tyrosine Phosphatases , Animals , Mice , Acute Lung Injury/metabolism , Extracellular Traps/metabolism , Lung/metabolism , Mice, Inbred C57BL , Mice, Knockout , Neutrophils , Protein Tyrosine Phosphatases/metabolism , Immediate-Early Proteins/metabolismABSTRACT
Osteopontin (OPN) is a multifunctional protein that plays a pivotal role in the immune system. It is involved in various biological processes, including cell adhesion, migration and survival. The study of the immunomodulatory effects of OPN is of paramount importance due to its potential therapeutic applications. A comprehensive understanding of how OPN regulates the immune response could pave the way for the development of novel treatments for a multitude of diseases, including autoimmune disorders, infectious diseases and cancer. Therefore, in the following paper, we provide a systematic overview of OPN and its immunoregulatory roles in various diseases, laying the foundation for the development of OPN-based therapies in the future.
Subject(s)
Neoplasms , Osteopontin , Humans , Osteopontin/metabolism , Cell Adhesion , ImmunityABSTRACT
Mast cells are phenotypically and functionally heterogeneous, and their state is possibly controlled by local microenvironment. Therefore, specific analyses are needed to understand whether mast cells function as powerful participants or dispensable bystanders in specific diseases. Here, we show that degranulation of mast cells in inflammatory synovial tissues of patients with rheumatoid arthritis (RA) is induced via MAS-related G protein-coupled receptor X2 (MRGPRX2), and the expression of MHC class II and costimulatory molecules on mast cells are upregulated. Collagen-induced arthritis mice treated with a combination of anti-IL-17A and cromolyn sodium, a mast cell membrane stabilizer, show significantly reduced clinical severity and decreased bone erosion. The findings of the present study suggest that synovial microenvironment-influenced mast cells contribute to disease progression and may provide a further mast cell-targeting therapy for RA.
Subject(s)
Arthritis, Rheumatoid , Synoviocytes , Humans , Mice , Animals , Mast Cells/metabolism , Arthritis, Rheumatoid/metabolism , Synoviocytes/metabolism , Synovial Membrane/metabolism , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Nerve Tissue Proteins/metabolism , Receptors, Neuropeptide/metabolismABSTRACT
Psoriatic arthritis (PsA) is a disease that transformed from psoriasis (PsO), and its underlying mechanisms are still not fully understood. Overactivation of the immune system is a key factor driving inflammatory diseases. Our goal is to define the unbalanced subsets of peripheral blood CD4 +T cells between PsO and PsA patients. Blood samples from 43 patients (23 PsA and 20 PsO) and 36 healthy donors (HD) were studied. Peripheral blood mononuclear cells (PBMC) were separated from blood and underwent fluorescent staining to assess CD4+T cell subsets by flow cytometry. We found that frequencies of various CD4+T cells including Th1, Th2, Th17, and Tfh were higher in the patients with PsO or PsA than those of healthy donors, indicating the general expansion of CD4+T cells in inflammatory conditions. More importantly, we observed the significant imbalance of Th1/Th2 between patients with PsO and PsA. Pearson correlation analysis showed that Th1/Th2 ratio was positively correlated with disease activity in psoriatic arthritis (DAPSA), Tfh/Tfr ratio was positively correlated with DAPSA score and visual analogue scale (VAS) score in PsA patients. Together, our results highlight the CD4+T cell changes in the transition from PsO to PsA, may contribute to early assessment and intervention.
Subject(s)
Arthritis, Psoriatic , Psoriasis , Humans , Leukocytes, Mononuclear , CD4-Positive T-Lymphocytes , T-Lymphocyte SubsetsABSTRACT
PURPOSE: Femoral nerve block (FNB) is widely used in patients undergoing knee arthroscopy. However, the most commonly used concentration of ropivacaine (0.2% or above) may cause an unexpected decrease in the muscle strength of the quadriceps. Therefore, a lower concentration of ropivacaine (0.1%) for FNB was administered to investigate the effect on quadriceps strength and postoperative pain after knee arthroscopy. METHODS: This was a double-blind, randomized, controlled trial (ChiCTR2000041404). A total of 83 patients scheduled for elective knee arthroscopy were randomized to receive 0.1% or 0.2% ropivacaine for FNB under ultrasound guidance. The primary outcomes were quadriceps strength and numerical rating scale (NRS) pain score. Quadriceps strength was measured before surgery and 6 h and 24 h after surgery, while NRS score was recorded before surgery, at the postanaesthesia care unit (PACU), and 6 h and 24 h after surgery. Multiple linear regression tests were used to compare the differences in quadriceps strength and NRS score between the two groups. Two-factor analysis of variance, using the factors group and time of measurement, was used for repeated NRS scores. Secondary outcomes included knee mobility, side effects, patient satisfaction, and length of hospital stay. RESULTS: The mean (SD) quadriceps strength at 6 h after surgery was 7.5 (5.7) kg for the 0.1% ropivacaine group and 3.0 (4.4) kg for the 0.2% ropivacaine group. The mean difference adjusted for baseline characteristics was - 5.2 (95% CI - 7.2 to - 3.1) kg (P < 0.001). There was no significant difference between the two groups in quadriceps strength at 24 h after surgery. The mean differences in the average NRS score and maximum NRS score in the PACU were - 0.6 (P = 0.008) and - 1.0 (P < 0.001), respectively. There was no significant difference in NRS score at 6 h or 24 h after surgery. Two-factor analysis of variance showed no significant difference in the interaction factors of time and group for average NRS score and maximum NRS score. CONCLUSIONS: Compared with 0.2% ropivacaine, 0.1% ropivacaine for FNB preserved quadriceps strength at 6 h after knee arthroscopy while providing similar analgesic effects. LEVEL OF EVIDENCE: I.
Subject(s)
Anesthetics, Local , Nerve Block , Humans , Ropivacaine , Anesthetics, Local/therapeutic use , Femoral Nerve , Arthroscopy/adverse effects , Nerve Block/adverse effects , Pain, Postoperative/drug therapy , Pain, Postoperative/prevention & control , Pain, Postoperative/etiology , Quadriceps Muscle/physiology , Analgesics/therapeutic use , Double-Blind Method , Analgesics, Opioid/therapeutic useABSTRACT
Atopic dermatitis (AD) is a common inflammatory skin disorder. Mast cells play an important role in AD because they regulate allergic reactions and inflammatory responses. However, whether and how the modulation of mast cell activity affects AD has not been determined. In this study, we aimed to determine the effects and mechanisms of 3-O-cyclohexanecarbonyl-11-keto-ß-boswellic acid (CKBA). This natural compound derivative alleviates skin inflammation by inhibiting mast cell activation and maintaining skin barrier homeostasis in AD. CKBA markedly reduced serum IgE levels and alleviated skin inflammation in calcipotriol (MC903)-induced AD mouse model. CKBA also restrained mast cell degranulation both in vitro and in vivo. RNA-seq analysis revealed that CKBA downregulated the extracellular signal-regulated kinase (ERK) signaling in BM-derived mast cells activated by anti-2,4-dinitrophenol/2,4-dinitrophenol-human serum albumin. We proved that CKBA suppressed mast cell activation via ERK signaling using the ERK activator (t-butyl hydroquinone) and inhibitor (selumetinib; AZD6244) in AD. Thus, CKBA suppressed mast cell activation in AD via the ERK signaling pathway and could be a therapeutic candidate drug for AD.
Subject(s)
Dermatitis, Atopic , Mice , Humans , Animals , Dermatitis, Atopic/drug therapy , Mast Cells/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Immunoglobulin E/metabolism , Signal Transduction , Inflammation/metabolism , Dinitrophenols/metabolism , Dinitrophenols/pharmacology , Dinitrophenols/therapeutic use , Cytokines/metabolismABSTRACT
Fibroblast-like synoviocytes (FLS) mediate many pathological processes in rheumatoid arthritis (RA), including pannus formation, bone erosion, and inflammation. RA FLS have unique aggressive phenotypes and exhibit several tumor cell-like characteristics, including hyperproliferation, excessive migration and invasion. Casein kinase 2 (CK2) is reportedly overexpressed in numerous tumor types, and targeted inhibition of CK2 has therapeutic benefits for tumors. However, the expression level of CK2 and its functions in RA FLS remain unclear. Herein, we aimed to elucidate whether CK2 is responsible for the aggressive phenotypes of RA FLS and whether targeted therapy can alleviate the severity of RA. We found that CK2 subunits were elevated in RA FLS compared with osteoarthritis FLS, and the activity of CK2 also markedly increased in RA FLS. Targeted inhibition of CK2 using CX-4945 suppressed RA FLS proliferation through cell cycle arrest. Cell migration and invasion were also inhibited by CX-4945 treatment. Moreover, CX-4945 reduced Interleukin-6 (IL-6), CC motif chemokine ligand 2 (CCL2) and Matrix metalloproteinase-3 (MMP-3) secretion in RA FLS. Further proteomic investigation revealed that p53 signaling pathway significantly changes after CX-4945 treatment in RA FLS. The siRNA-mediated p53 knockdown partly abolished the anti-proliferation and reduced IL-6, MMP-3 secretion effects of CX-4945. Furthermore, CX-4945 administration alleviates arthritis severity in CIA mice. Collectively, our results demonstrated the abnormal elevation of CK2 and its positive association with abnormal phenotypes in RA FLS. Our novel findings suggest the possible therapeutic potential of CX-4945 for RA.
Subject(s)
Arthritis, Rheumatoid , Synoviocytes , Mice , Animals , Casein Kinase II/metabolism , Casein Kinase II/pharmacology , Casein Kinase II/therapeutic use , Matrix Metalloproteinase 3/metabolism , Tumor Suppressor Protein p53/metabolism , Interleukin-6/metabolism , Proteomics , Cell Proliferation , Cells, Cultured , Arthritis, Rheumatoid/metabolism , Fibroblasts , Patient Acuity , Synovial Membrane/pathologyABSTRACT
In this study, micron-sized monodisperse SiO2 microspheres were used as sacrificial templates, and chitosan/polylactic acid (CTS/PLA) bio-microcapsules were produced using the layer-by-layer (LBL) assembly method. Microcapsules isolate bacteria from their surroundings, forming a separate microenvironment and greatly improving microorganisms' ability to adapt to adverse environmental conditions. Morphology observation indicated that the pie-shaped bio-microcapsules with a certain thickness could be successfully prepared through LBL assembly method. Surface analysis showed that the LBL bio-microcapsules (LBMs) had large fractions of mesoporous. The biodegradation experiments of toluene and the determination of toluene degrading enzyme activity were also carried out under external adverse environmental conditions (i.e., unsuitable initial concentrations of toluene, pH, temperature, and salinity). The results showed that the removal rate of toluene by LBMs can basically reach more than 90% in 2 days under adverse environmental conditions, which is significantly higher than that of free bacteria. In particular, the removal rate of toluene by LBMs can reach four times that of free bacteria at pH 3, which indicates that LBMs maintain a high level of operational stability for toluene degradation. Flow cytometry analysis showed that LBL microcapsules could effectively reduce the death rate of the bacteria. The results of the enzyme activity assay showed that the enzyme activity was significantly stronger in the LBMs system than in the free bacteria system under the same unfavorable external environmental conditions. In conclusion, the LBMs were more adaptable to the uncertain external environment, which provided a feasible bioremediation strategy for the treatment of organic contaminants in actual groundwater.
ABSTRACT
Soil erosion and nutrient loss are important environmental and ecological problems in the Dianchi watershed in southwestern China. Woodlands-the primary land type in the Dianchi watershed-play an important ecological role in controlling soil and water loss. In this study, we compared soil erosion and loss of total organic carbon (TOC), total nitrogen (TN), and total phosphorus (TP) in woodlands of different ages, i.e., young forest, medium forest, and near-mature forest, at the Dongda River catchment in south-western Dianchi watershed. Furthermore, changes in stoichiometries in soil were analyzed. The average degree of erosion of each forest age stage was below moderate. Based on the non-arable soil erosion modulus models of 137Cs and 210Pbex, the soil erosion rates decreased gradually with the increasing forest age. The forest age affected soil nutrient distribution and loss. The losses of TOC and TP gradually decreased, while the losses of TN first increased and then decreased with the growth of forest age. TOC, TN, and TP were enriched in the topsoil. Forest age affected soil stoichiometry and soil nutrient supply level. In general, the forest can effectively reduce soil erosion and nutrient loss in the red soil area with the forest age increasing.
Subject(s)
Environmental Monitoring , Soil Erosion , Forests , China , Soil , Nitrogen/analysis , Phosphorus/analysisABSTRACT
T follicular helper (Tfh) cells with the phenotype of mainly expressing surface molecules C-X-C motif chemokine receptor type 5 (CXCR5), inducible co-stimulator (ICOS), secreting cytokine interleukin-21 (IL-21) and requiring the transcription factor B cell lymphoma 6 (BCL-6) have been recently defined as a new subset of CD4+ T cells. They exist in germinal centers (GCs) of lymphoid organs and in peripheral blood. With the ability to promote B cell development, GC formation and antibody production, Tfh cells play critical roles in the pathogenesis of many autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), primary Sjögren's syndrome (pSS), etc. The aberrant proliferation and function of Tfh cells will cause the pathological process like autoantibody production and tissue injury. In this paper, we review the recent advances in Tfh cell biology and their roles in autoimmune diseases, with a mention of their use as therapeutic targets, which will shed more light on the pathogenesis and treatment of certain autoimmune diseases.
Subject(s)
Arthritis, Rheumatoid , T Follicular Helper Cells , Humans , T-Lymphocytes, Helper-Inducer , Cytokines , Germinal CenterABSTRACT
Inflammation leads to systemic osteoporosis or local bone destruction, however, the underlying molecular mechanisms are still poorly understood. In this study, we report that PRL2 is a negative regulator of osteoclastogenesis and bone absorption. Mice with PRL2 deficiency exhibit a decrease in bone volume and an increase in osteoclast numbers. PRL2 negatively regulates RANKL-induced reactive oxygen species production through the activation of RAC1, thus PRL2 deficient osteoclast precursors have both increased osteoclast differentiation ability and bone resorptive capacity. During inflammation, oxidized PRL2 is a selected substrate of HSC70 and conditions of oxidative stress trigger rapid degradation of PRL2 by HSC70 mediated endosomal microautophagy and chaperone-mediated autophagy. Ablation of PRL2 in mouse models of inflammatory bone disease leads to an increase in the number of osteoclasts and exacerbation of bone damage. Moreover, reduced PRL2 protein levels in peripheral myeloid cells are highly correlated with bone destruction in a mouse arthritis model and in human rheumatoid arthritis, while the autophagy inhibitor hydroxychloroquine blocked inflammation-induced PRL2 degradation and bone destruction in vivo. Therefore, our findings identify PRL2 as a new regulator in osteoimmunity, providing a link between inflammation and osteoporosis. As such, PRL2 is a potential therapeutic target for inflammatory bone disease and inhibition of HSC70 mediated autophagic degradation of PRL2 may offer new therapeutic tools for the treatment of inflammatory bone disease.
Subject(s)
Bone Resorption , Osteoporosis , Animals , Humans , Mice , Autophagy , Bone Resorption/metabolism , Cell Differentiation/physiology , Disease Models, Animal , Inflammation/metabolism , Osteoclasts/metabolism , Osteogenesis , Osteoporosis/metabolism , RANK Ligand/metabolism , HSC70 Heat-Shock Proteins/metabolismABSTRACT
Pollution from polycyclic aromatic hydrocarbons (PAHs) spreads and changes worldwide. The pollution evolution in the regional water environment evolves in response to multiple factors, requiring considerable attention. PAH heterogeneity in the sediment core from Chaihe Reservoir was investigated to indicate dynamic changes in PAH pollution levels and sources and propose recommendations for controlling PAHs. Dynamic PAH patterns showed that the overall decline in PAH pollution was in association with local anthropogenic activities, temperature, and precipitation over the period 1863-2018. Nevertheless, coal, oil, and natural gas consumptions still played significant roles in transferring PAHs to the reservoir. Meanwhile, there were dominant local origins, including grass, wood, and coal combustion. The results highlight that the joint action of natural and anthropogenic interventions mitigated PAH pollution in the reservoir. Promoting improved fuels, new energy vehicles, and cleaner energy may further lower PAH pollution.
Subject(s)
Polycyclic Aromatic Hydrocarbons , Water Pollutants, Chemical , Water Pollutants, Chemical/analysis , Geologic Sediments , Environmental Monitoring/methods , Coal/analysis , ChinaABSTRACT
γ-Tocotrienol (GT3), a member of the vitamin E family, is well known for its medicinal value in clinical treatments. However, the role of GT3 in T helper 17 (Th17)/regulatory T cell (Treg) differentiation and function is not fully understood. Here, we demonstrated that GT3 suppressed Th17 differentiation in vitro by inhibiting signal transducer and activator of transcription 3 (STAT3) phosphorylation in the interleukin 6 (IL-6)/Janus kinase (JAK)/STAT3 signaling pathway. GT3 also inhibited HIF1A expression in Th17 metabolism. Additionally, we showed that GT3 treatment inhibited disease aggravation in an imiquimod (IMQ)-induced psoriasis-like mouse model by reducing the percentage of Th17 cells in the spleen in vivo. The findings of this study demonstrated the effects of GT3 on Th17 cells through the STAT3 signaling pathway.
Subject(s)
Janus Kinases , STAT3 Transcription Factor , Animals , Cell Differentiation , Chromans , Imiquimod/pharmacology , Interleukin-17/metabolism , Interleukin-6/metabolism , Mice , STAT3 Transcription Factor/metabolism , Signal Transduction , Th17 Cells , Vitamin E/analogs & derivatives , Vitamin E/metabolism , Vitamin E/pharmacologyABSTRACT
This work developed an environmentally-friendly soil remediation method based on BC and g-C3N4, and demonstrated the technical feasibility of remediating petroleum-contaminated soil with biochar/graphite carbon nitride (BC/g-C3N4). The synthesis of BC/g-C3N4 composites was used for the removal of TPH in soil via adsorption and photocatalysis. BC, g-C3N4, and BC/g-C3N4 have been characterized by scanning electron microscopy (SEM), Brunauer-Emmett-Teller surface area analyzer (BET), FT-IR, and X-ray diffraction (XRD). BC/g-C3N4 facilitates the degradation due to reducing recombination and better electron-hole pair separation. BC, g-C3N4, and BC/g-C3N4 were tested for their adsorption and photocatalytic degradation capacities. Excellent and promising results are brought out by an apparent synergism between adsorption and photocatalysis. The optimum doping ratio of 1:3 between BC and g-C3N4 was determined by single-factor experiments. The removal rate of total petroleum hydrocarbons (TPH) by BC/g-C3N4 reached 54.5% by adding BC/g-C3N4 at a dosing rate of 0.08 g/g in a neutral soil with 10% moisture content, which was 2.12 and 1.95 times of BC and g-C3N4, respectively. The removal process of TPH by BC/g-C3N4 conformed to the pseudo-second-order kinetic model. In addition, the removal rates of different petroleum components in soil were analyzed in terms of gas chromatography-mass spectrometry (GC-MS), and the removal rates of nC13-nC35 were above 90% with the contaminated soil treated by BC/g-C3N4. The radical scavenger experiments indicated that superoxide radical played the major role in the photocatalytic degradation of TPH. This work definitely demonstrates that the BC/g-C3N4 composites have great potential for application in the remediation of organic pollutant contaminated soil.
Subject(s)
Petroleum , Charcoal , Hydrocarbons/analysis , Petroleum/analysis , Soil/chemistry , Spectroscopy, Fourier Transform InfraredABSTRACT
Lake sediment records the evolution process of the interaction between human and nature. It is important to master the lacustrine sedimentation rate for the ecological environment assessment of catchment. A 60-cm sediment core was collected in the Da River Reservoir during 2019 to analyze radionuclides (210Pb and 137Cs) massic activities, grain size, total organic carbon (TOC), total nitrogen (TN), total phosphorus (TP), and metals (Mn, Cu, Al, and Pb) mass fractions to reconstruct the response of sedimentation rate to environmental evolution. The environmental changes in the small catchment were classified into the following three stages through cluster analysis (CA) for geochemical parameters in the sediment core: phase I (1881-1985), phase II (1987-1999), and phase III (2000-2018). The average depth sedimentation rates (ADSRs) of the three stages were 0.33, 0.90, and 1.50 cm/year, respectively. The sedimentation rates increased from the bottom to the surface layer, indicating that the exogenous inputs into the reservoir have been occurring. The sediment deposition in phase III was strongly disturbed by the environmental changes (such as warmer climate and intensified land use). Therefore, sedimentation rates showed a rapid increase. Both Pearson correlation analysis and redundancy analysis (RDA) showed that sedimentation rates were positively correlated with climatic factors, particle size, nutrients and metals mass fractions, elemental ratios, and socioeconomic parameters. Sedimentation rates show high sensitivity to anthropogenic activities and climatic change, which can be used to reconstruct the environmental evolution process at a small catchment scale.
Subject(s)
Geologic Sediments , Rivers , Humans , Geologic Sediments/analysis , Environmental Monitoring , Lead/analysis , Lakes/analysis , Phosphorus/analysis , Nitrogen/analysis , Carbon/analysis , ChinaABSTRACT
Prostaglandin E2 (PGE2) is a lipid mediator derived from the fatty acid arachidonic acid. As an essential inflammatory factor, PGE2 has a critical impact on immune regulation through the prostanoid E (EP) receptor pathway. T cells, including CD4+ and CD8+ T cell subsets, play crucial roles in the adaptive immune response. Previous studies have shown that PGE2 is involved in regulating CD4+ T cell differentiation and inflammatory cytokine production via the EP receptor pathway, thereby affecting the development of diseases mediated by CD4+ T cells. In this review, we summarize the signaling pathway of PGE2 and describe the relationship between PGE2 and T cell differentiation. Hence, this review may provide important evidence for immune therapies and may even promote the development of biomedicines.
Subject(s)
Dinoprostone/physiology , T-Lymphocytes/cytology , Cell Differentiation , Humans , Receptors, Prostaglandin E/physiology , Signal Transduction/physiologyABSTRACT
Epigallocatechin-3 gallate (EGCG) is a polyphenolic component of tea and has potential curative effects in patients with autoimmune diseases. Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS). It remains unknown whether EGCG can regulate macrophage subtypes in MS. Here we evaluated the effects of EGCG in experimental autoimmune encephalomyelitis (EAE), MS mouse model. We found that EGCG treatment reduced EAE severity and macrophage inflammation in the CNS. Moreover, EAE severity was well correlated with the ratio of M1 to M2 macrophages, and EGCG treatment suppressed M1 macrophage-mediated inflammation in spleen. In vitro experiments showed that EGCG inhibited M1 macrophage polarization, but promoted M2 macrophage polarization. These effects were likely to be related to the inhibition of nuclear factor-κB signaling and glycolysis in macrophages by EGCG in macrophages. Overall, these findings provided important insights into the mechanisms through which EGCG may mediate MS.
Subject(s)
Catechin/analogs & derivatives , Encephalomyelitis, Autoimmune, Experimental/therapy , Macrophages/metabolism , Multiple Sclerosis/therapy , Neuroprotective Agents/therapeutic use , Animals , Catechin/therapeutic use , Cell Differentiation , Cytokines/metabolism , Glycolysis , Humans , Macrophages/immunology , Male , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , Signal Transduction , Tea , Th1 Cells/immunology , Th2 Cells/immunologyABSTRACT
Intestinal stromal cells are known to modulate the propagation and differentiation of intestinal stem cells1,2. However, the precise cellular and molecular mechanisms by which this diverse stromal cell population maintains tissue homeostasis and repair are poorly understood. Here we describe a subset of intestinal stromal cells, named MAP3K2-regulated intestinal stromal cells (MRISCs), and show that they are the primary cellular source of the WNT agonist R-spondin 1 following intestinal injury in mice. MRISCs, which are epigenetically and transcriptomically distinct from subsets of intestinal stromal cells that have previously been reported3-6, are strategically localized at the bases of colon crypts, and function to maintain LGR5+ intestinal stem cells and protect against acute intestinal damage through enhanced R-spondin 1 production. Mechanistically, this MAP3K2 specific function is mediated by a previously unknown reactive oxygen species (ROS)-MAP3K2-ERK5-KLF2 axis to enhance production of R-spondin 1. Our results identify MRISCs as a key component of an intestinal stem cell niche that specifically depends on MAP3K2 to augment WNT signalling for the regeneration of damaged intestine.
Subject(s)
Intestinal Mucosa/cytology , MAP Kinase Kinase Kinase 2/metabolism , Stem Cell Niche , Stromal Cells/cytology , Animals , Antigens, CD34 , Colitis/pathology , Colitis/prevention & control , Epigenesis, Genetic , Female , Intestinal Mucosa/pathology , Kruppel-Like Transcription Factors/metabolism , Male , Mice , Reactive Oxygen Species/metabolism , Tetraspanin 28 , Thrombospondins/biosynthesis , Thrombospondins/metabolism , Thy-1 AntigensABSTRACT
BACKGROUND: The four major RNA adenosine modifications, i.e., m6A, m1A, alternative polyadenylation, and adenosine-to-inosine RNA editing, are mediated mostly by the "writer" enzymes and constitute critical mechanisms of epigenetic regulation in immune response and tumorigenesis. However, the cross-talk and potential roles of these "writers" in the tumor microenvironment (TME), drug sensitivity, and immunotherapy remain unknown. METHODS: We systematically characterized mRNA expression and genetic alterations of 26 RNA modification "writers" in colorectal cancer (CRC), and evaluated their expression pattern in 1697 CRC samples from 8 datasets. We used an unsupervised clustering method to assign the samples into two patterns of expression of RNA modification "writers". Subsequently, we constructed the RNA modification "writer" Score (WM_Score) model based on differentially expressed genes (DEGs) responsible for the RNA modification patterns to quantify the RNA modification-related subtypes of individual tumors. Furthermore, we performed association analysis for WM_Score and characteristics of TME, consensus molecular subtypes (CMSs), clinical features, transcriptional and post-transcriptional regulation, drug response, and the efficacy of immunotherapy. RESULTS: We demonstrated that multi-layer alterations of RNA modification "writer" are associated with patient survival and TME cell-infiltrating characteristics. We identified two distinct RNA modification patterns, characterized by a high and a low WM_Score. The WM_Score-high group was associated with worse patient overall survival and with the infiltration of inhibitory immune cells, such as M2 macrophages, EMT activation, and metastasis, while the WM_Score-low group was associated with a survival advantage, apoptosis, and cell cycle signaling pathways. WM_Score correlated highly with the regulation of transcription and post-transcriptional events contributing to the development of CRC. In response to anti-cancer drugs, WM_Score highly negatively correlated (drug sensitive) with drugs which targeted oncogenic related pathways, such as MAPK, EGFR, and mTOR signaling pathways, positively correlated (drug resistance) with drugs which targeted in apoptosis and cell cycle. Importantly, the WM_Score was associated with the therapeutic efficacy of PD-L1 blockade, suggesting that the development of potential drugs targeting these "writers" to aid the clinical benefits of immunotherapy. CONCLUSIONS: Our study is the first to provide a comprehensive analysis of four RNA modifications in CRC. We revealed the potential function of these writers in TME, transcriptional and post-transcriptional events, and identified their therapeutic liability in targeted therapy and immunotherapy. This work highlights the cross-talk and potential clinical utility of RNA modification "writers" in cancer therapy.
Subject(s)
Biomarkers, Tumor , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , Pharmacogenetics , RNA Processing, Post-Transcriptional , Tumor Microenvironment/genetics , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Combined Modality Therapy , Computational Biology/methods , Disease Management , Disease Susceptibility , Epithelial-Mesenchymal Transition , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Lymphocytes, Tumor-Infiltrating/pathology , Pharmacogenetics/methods , Prognosis , Proportional Hazards Models , RNA Processing, Post-Transcriptional/drug effects , Transcription, Genetic , Transcriptome , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunologyABSTRACT
The fungal community and soil geochemical, physical and biological parameters were analyzed, respectively, in bauxite residues (BRs) treated with organic matter and vermiculite/fly ash by phylogenetic analysis of ITS-18 S rRNA, community level physiological profiles (CLPP) and so on. The results indicated that after amendment of the BR, microbial utilization of carbohydrates and their enzyme activities were significantly increased, but fungal compositions at the phylum level were similar and dominated by the phylum of Ascomycota (82.05-98.96%, RA: relative abundance) after one year of incubation. The fungal taxa in the amended BR treatments, however, show significantly less alpha and beta diversity compared with the reference soils, although they still harbor a substantial novel taxon. The combined amendment of organic matter (OM) and vermiculite/fly ash significantly increases the fungal taxa at the genus and species level compared with solely OM amendment. The results of the following canonical correspondence analysis found that, over 90% variation of the fungal community could be explained by pH, OM and mean weight diameter (MWD) of aggregates; but the biological indicators, including urease (UR), dehydrogenase (DHA) and the value of average well color development (AWCD) could explain only 50% variation of the fungal flora in BRs. This paper indicated that resilience of fungal community in BRs was positively correlated with the BRs' improvement in fertility as well as biogeochemical properties, but alkalinity must be firstly decreased to the target level of BRs' rehabilitation.