N-ethyl-N-nitrosourea (ENU)-induced C-terminal truncation of Runx3 results in autoimmune colitis associated with Th17/Treg imbalance.

Inflammatory bowel disease (IBD) is a chronic and progressive inflammatory intestinal disease that affects people around the world. The primary cause of IBD is an imbalance in the host immune response to intestinal flora. Several human genes, including IL10, STAT3, IRGM, ATG16L1, NOD2 and RUNX3, are associated with inappropriate immune responses in IBD. It has been reported that homozygous Runx3-knockout (ko) mice spontaneously develop colitis. However, the high mortality rate in these mice within the first two weeks makes it challenging to study the role of Runx3 in colitis. To address this issue, a spontaneous colitis (SC) mouse model carrying a C-terminal truncated form of Runx3 with Tyr319stop point mutation has been generated. After weaning, SC mice developed spontaneous diarrhea and exhibited prominent enlargement of the colon, accompanied by severe inflammatory cell infiltration. Results of immunofluorescence staining showed massive CD4+ T cell infiltration in the inflammatory colon of SC mice. Colonic IL-17A mRNA expression and serum IL-17A level were increased in SC mice. CD4+ T cells from SC mice produced stronger IL-17A than those from wildtype mice in Th17-skewing conditions in vitro. In addition, the percentages of Foxp3+ Treg cells as well as the RORγt+Foxp3+ Treg subset, known for its role in suppressing Th17 response in the gut, were notably lower in colon lamina propria of SC mice than those in WT mice. Furthermore, transfer of total CD4+ T cells from SC mice, but not from wildtype mice, into Rag1-ko host mice resulted in severe autoimmune colitis. In conclusion, the C-terminal truncated Runx3 caused autoimmune colitis associated with Th17/Treg imbalance. The SC mouse model is a feasible approach to investigate the effect of immune response on spontaneous colitis.

Injectable, Antioxidative, and Tissue-Adhesive Nanocomposite Hydrogel as a Potential Treatment for Inner Retina Injuries.

Reactive oxygen species (ROS) have been recognized as prevalent contributors to the development of inner retinal injuries including optic neuropathies such as glaucoma, non-arteritic anterior ischemic optic neuropathy, traumatic optic neuropathy, and Leber hereditary optic neuropathy, among others. This underscores the pivotal significance of oxidative stress in the damage inflicted upon retinal tissue. To combat ROS-related challenges, this study focuses on creating an injectable and tissue-adhesive hydrogel with tailored antioxidant properties for retinal applications. GelCA, a gelatin-modified hydrogel with photo-crosslinkable and injectable properties, is developed. To enhance its antioxidant capabilities, curcumin-loaded polydopamine nanoparticles (Cur@PDA NPs) are incorporated into the GelCA matrix, resulting in a multifunctional nanocomposite hydrogel referred to as Cur@PDA@GelCA. This hydrogel exhibits excellent biocompatibility in both in vitro and in vivo assessments, along with enhanced tissue adhesion facilitated by NPs in an in vivo model. Importantly, Cur@PDA@GelCA demonstrates the potential to mitigate oxidative stress when administered via intravitreal injection in retinal injury models such as the optic nerve crush model. These findings underscore its promise in advancing retinal tissue engineering and providing an innovative strategy for acute neuroprotection in the context of inner retinal injuries.

Bimetallic nickel complexes containing imidazole-based phenolate ligands as efficient catalysts for the copolymerization of carbon dioxide with epoxides.

The utilization of hexadentate imidazole-derived diamine-bisphenolate ligands to construct structurally well-defined bimetallic nickel catalysts that enable the mediation of the copolymerization of carbon dioxide with alicyclic epoxides was reported for the first time. A series of dinickel carboxylate/nitrophenolate complexes were facilely prepared through a one-pot procedure and their structures were fully determined by single crystal X-ray structural analysis. Dinickel complexes 1-10 were used as single-component catalysts, and were evaluated for the copolymerization of CO2 and cyclohexene oxide (CHO), for which acetato-incorporated complex 1 was proved to exhibit the best activity. Not only has the controllability of binickel catalyst 1 for CO2/CHO copolymerization been demonstrated, but also an "immortal" character for the same polymerization has been realized. Furthermore, detailed kinetic studies of polymerization catalysis of this type were undertaken, and the kinetics results revealed a first-order dependence on both Ni complex 1 and CHO concentrations. This is a successful example of the introduction of the easily accessible nitrogen-heterocycle group, the imidazole moiety, into phenolate ligands for the development of high-performance homogeneous catalysts towards the bimetallic complex-catalyzed copolymerization of CO2 and epoxides.

Bimetallic Nickel Complexes as Effective and Versatile Catalysts for Copolymerization of Epoxides with Carbon Dioxide or Phthalic Anhydride: Catalysis and Kinetics.

This study reported three novel structurally well-characterized dihalide dinuclear nickel complexes containing benzotriazole-based 1,3-diamine-linked bisphenolate ligands, which were high-performance catalysts for ring-opening copolymerization (ROCOP) of cyclohexene oxide (CHO) and carbon dioxide (CO2). The dinickel diiodo 3 was shown to catalyze CO2 copolymerization of CHO with high activity (turnover frequency up to 2250 h-1), excellent selectivity (>99% polycarbonates, >99% carbonate repeated units), and good molecular weight controllability. Apart from CO2/CHO copolymerization, the most active complex 3 was found to effectively catalyze ROCOP of CHO with phthalic anhydride (PA). Not only has the controllable manner of 3 for PA/CHO copolymerization been proven but also a broad substrate scope for PA copolymerization of epoxides by the same complex has been achieved. Diverse terminal or internal epoxides were demonstrated to copolymerize PA by 3, producing the corresponding semiaromatic polyesters with good activity and excellent product selectivity. Kinetic studies for CHO copolymerization of CO2 or PA mediated by 3 were systematically investigated. For kinetics of PA/CHO copolymerization, it allowed us to propose the rate equation of -d[CHO]/dt = kp[3]1[PA]0[CHO]1, and such catalysis displayed a first-order dependence on both dinickel complex and CHO concentrations as well as a zero order for PA. This work offers a bimetallic dihalide nickel complex as an efficient and versatile catalyst for two different types of copolymerization catalysis.

Evolution of nanostructured skin patches towards multifunctional wearable platforms for biomedical applications.

Recent advances in the field of skin patches have promoted the development of wearable and implantable bioelectronics for long-term, continuous healthcare management and targeted therapy. However, the design of electronic skin (e-skin) patches with stretchable components is still challenging and requires an in-depth understanding of the skin-attachable substrate layer, functional biomaterials and advanced self-powered electronics. In this comprehensive review, we present the evolution of skin patches from functional nanostructured materials to multi-functional and stimuli-responsive patches towards flexible substrates and emerging biomaterials for e-skin patches, including the material selection, structure design and promising applications. Stretchable sensors and self-powered e-skin patches are also discussed, ranging from electrical stimulation for clinical procedures to continuous health monitoring and integrated systems for comprehensive healthcare management. Moreover, an integrated energy harvester with bioelectronics enables the fabrication of self-powered electronic skin patches, which can effectively solve the energy supply and overcome the drawbacks induced by bulky battery-driven devices. However, to realize the full potential offered by these advancements, several challenges must be addressed for next-generation e-skin patches. Finally, future opportunities and positive outlooks are presented on the future directions of bioelectronics. It is believed that innovative material design, structure engineering, and in-depth study of fundamental principles can foster the rapid evolution of electronic skin patches, and eventually enable self-powered close-looped bioelectronic systems to benefit mankind.

CD8 + T cell memory is sustained in mice by hepatic stellate cells.

BACKGROUND AND AIMS: Long-lasting immunological memory is the ultimate goal of vaccination. Homeostatic maintenance of memory CD8 + cytotoxic T cells (MemCD8TCs) is thought to be mediated by IL-15/IL-15R heterodimer (15HD)-expressing myeloid cells. Nonmyeloid hepatic stellate cells (HSCs) also express 15HD, but their role in maintaining MemCD8TC homeostasis is unknown. APPROACH AND RESULTS: We engineered a genetically engineered mouse in which IL-15R complementary DNA (cDNA) had been inserted in-frame with lecithin-retinol acyltransferase gene and bred onto an IL-15R-KO (15R-KO) genetic background (L15R) that expressed IL-15R in HSCs at normal levels, but not in other liver cells. Outside of the liver of L15R mice, IL-15R expression was found in a number of organs, but not in dendritic cells and macrophages. The low IL-15R expression in the bone marrow (BM) of L15R mice was eliminated by the reconstitution of lethally-irradiated L15R mice with 15R-KO BM to generate L15RC mice. Because MemCD8TC maintenance is mediated by 15HD, not empty IL-15R, 15HD content in L15R mice was determined and found for liver, lung, kidney, and heart. L15R and L15RC mice developed and maintained long-lasting, systemic antigen-specific MemCD8TCs that were efficacious against tumor growth and Listeria monocytogenes infection in an antigen-specific manner. Among the four organs with 15HD content, liver-associated MemCD8TCs were different from those found in the lung, kidney, and heart in two ways: (1) they were quantitatively the most numerous, and (2) they appeared uniquely in the form of clusters in a specialized structure, sinusoidal niches of the liver. CONCLUSIONS: The liver, the largest organ of the body, is endowed with the capability of effectuating long-lasting functional cytotoxic T cell memory.

Well-Defined and Highly Effective Nickel Catalysts Coordinated on Tridentate SNO Schiff-Base Derivatives for Alternating Copolymerization of Epoxides and Anhydrides.

A series of Ni complexes supported by SNO Schiff-base derivatives were synthesized in this study. Complex synthesis and characterization data are reported herein. Treatment of the pro-ligands [L1-H = 2-(((2-(methylthio)ethyl)imino)methyl)phenol, L2-H = 2,4-di-tert-butyl-6-(((2-(methylthio)ethyl)imino)methyl)phenol, L3-H = 2-(((2-(methylthio)ethyl)imino)methyl)-4,6-bis(2-phenylpropan-2-yl)phenol, L4-H = 4-bromo-2-(((2-(methylthio)ethyl)imino)methyl)phenol, and L5-H = 4-chloro-2-(((2-(methylthio)ethyl)imino)methyl)phenol] with Ni(OAc)2·4H2O in refluxing ethanol afforded six-coordinate mono-Ni(II) complexes [L2nNi] (n = 1-5). Noteworthy, a heptanuclear nickel(II) octacarboxylate species complex 6 and dinuclear nickel complex 6a resulted from treatment of L6-H [4-fluoro-2-(((2-(methylthio)ethyl)imino)methyl)phenol] with different metal precursors [Ni(OAc)2·4H2O for 6; NiBr2 for 6a] giving a quantitative yield. The reaction of nickel acetate tetrahydrate and L7-H to L9-H [L7-H = 2-methoxy-6-(((2-(methylthio)ethyl)imino)methyl)phenol, L8-H = 5-methoxy-2-(((2-(methylthio)ethyl)imino)methyl)phenol, and L9-H = 4-methoxy-2-(((2-(methylthio)ethyl)imino)methyl)phenol] produced the four-coordinate complexes [L2nNi] (n = 7-9). The highest performing catalyst was complex 3, which was highly efficient for the ring-opening copolymerization of phthalic anhydride (PA) and cyclohexene oxide (CHO) in the presence of a cocatalyst (4-dimethylaminopyridine). In addition, the same copolymerization conditions produced narrowly dispersed polyesters, with high selectivity and polymerization control. In addition to PA-CHO copolymerization, efficient diglycolic anhydride-PA and PA-propene oxide copolymerization was achieved under the same conditions. These catalysts are straightforward to produce and extend the scope of potential substrates.

Dinuclear Nickel Complexes Using Hexadentate Benzothiazole-Based Diamine-Bisphenolate Ligands: Highly Active Catalysts for Copolymerization of Carbon Dioxide with Epoxides.

We reported for the first time the utilization of hexadentate benzothiazole-based diamine-bisphenolate ligands to synthesize structurally well-characterized dinickel dicarboxylate complexes and studied their catalysis for copolymerization of carbon dioxide with epoxides. Dinickel carboxylate complexes having a 1,3-diamine-bridged backbone were demonstrated to be high-performance catalysts for alternating copolymerization of CO2 and cyclohexene oxide (CHO) with high product selectivity. Particularly, acetate-supported nickel complex 2 enabled us to promote such CO2-copolymerization of this kind with a maximum turnover frequency of up to 2600 h-1 and gave good molecular weight controllability under high-pressure conditions. It is worth noting that bimetallic Ni catalyst 2 was also capable of mediating the catalytic CO2-polymerization of alicyclic epoxides at atmospheric pressure. Kinetic investigations of CO2/CHO copolymerization by 2 allowed us to determine the rate equation of -d[CHO]/dt = kp[2]1[CHO]1, and such catalysis exhibited a first-order dependence on both dinickel complex and CHO concentrations.

Alternating Copolymerization of Carbon Dioxide with Epoxides Using Highly Active Dinuclear Nickel Complexes: Catalysis and Kinetics.

A novel series of well-defined dicarboxylate dinuclear nickel complexes containing benzotriazole based 1,3-diamine-bisphenolate (1,3-DiBTP) ligands were readily synthesized through a one-pot procedure, which were highly active single-component catalysts for copolymerization of CO2 and epoxides. X-ray structural determination of dinickel complexes 1-11 indicates that the DiBTP ligand acted as a N,O,N,N,O,N-hexadentate framework to chelate two nickel atoms, and two carboxylates are nonequivalently coordinated. The best benzoate-bonded dinickel catalyst 6 displayed the effective activity for both high-pressure and 1 atm CO2-copolymerization of cyclohexene oxide (CHO) in a controllable manner. Noteworthily, a high turnover frequency up to 9600 h-1 could be reached at 140 °C and a CO2 pressure of 20.7 bar utilizing a low catalyst loading of 0.01 mol %, and the same copolymerization conditions were capable of producing narrowly dispersed poly(cyclohexene carbonate) (PCHC) having >99% polycarbonate selectivity. In addition to CO2/CHO copolymerization, 4-vinyl-1,2-cyclohexene oxide or cyclopentene oxide was also applied to efficiently copolymerize CO2 under conditions of 80 °C and 20.7 bar initial CO2 pressure. Kinetic studies of CO2/CHO copolymerization catalyzed by 6 were investigated. Such polymerization revealed first-order dependence for both catalyst 6 and CHO concentrations, and the activation energy for PCHC generation by 6 is 57.69 kJ mol-1. A possible polymerization mechanism for CO2-copolymerization of CHO was proposed based on kinetics and structural studies of the obtained polycarbonates.

Ring-Opening Polymerization of ε-Caprolactone and Styrene Oxide-CO2 Coupling Reactions Catalyzed by Chelated Dehydroacetic Acid-Imine Aluminum Complexes.

A series of chelated dehydroacetic acid-imine-based ligands L1H~L4H was synthesized by reacting dehydroacetic acid with 2-t-butylaniline, (S)-1-phenyl-ethylamine, 4-methoxylbenzylamine, and 2-(aminoethyl)pyridine, respectively, in moderate yields. Ligands L1H~L4H reacted with AlMe3 in toluene to afford corresponding compounds AlMe2L1 (1), AlMe2L2 (2), AlMe2L3 (3), and AlMe2L4 (4). All the ligands and aluminum compounds were characterized by IR spectra, 1H and 13C NMR spectroscopy. Additionally, the ligands L1H~L4H and corresponding aluminum derivatives 1, 3, and 4 were characterized by single-crystal X-ray diffractometry. The catalytic activities using these aluminum compounds as catalysts for the ε-caprolactone ring-opening polymerization (ROP) and styrene oxide-CO2 coupling reactions were studied. The results show that increases in the reaction temperature and selective solvent intensify the conversions of ε-caprolactone to polycaprolactone. Regarding the coupling reactions of styrene oxide and CO2, the conversion rate is over 90% for a period of 12 h at 90 °C. This strategy dispenses the origination of cyclic styrene carbonates, which is an appealing concern because of the transformation of CO2 into an inexpensive, renewable and easy excess carbon feedstock.

Hierarchically Porous Carbon Materials from Self-Assembled Block Copolymer/Dopamine Mixtures.

Hierarchically porous carbon materials with interconnected frameworks of macro- and mesopores are desirable for electrochemical applications in biosensors, electrocatalysis, and supercapacitors. In this study, we report a facile synthetic route to fabricate hierarchically porous carbon materials by controlled macro- and mesophase separation of a mixture of polystyrene-block-poly(ethylene) and dopamine. The morphology of mesopores is tailored by controlling the coassembly of PS-b-PEO and dopamine in the acidic tetrahydrofuran-water cosolvent. HCl addition plays a critical role via enhancing the charge-dipole interactions between PEO and dopamine and suppressing the clustering and chemical reactions of dopamine in solution. As a result, subsequent drying can produce interpenetrated PS-b-PEO/DA mixtures without forming dopamine microsized crystallites. Dopamine oxidative polymerization induced by solvent annealing in NH4OH vapor enables the formation of percolating macropores. Subsequent pyrolysis to selectively remove the PS-b-PEO template from the complex can produce hierarchically porous carbon materials with interconnected frameworks of macro- and mesopores when pyrolysis is implemented at a low temperature or when DA is a minor component.

A reporter mouse for non-invasive detection of toll-like receptor ligands induced acute phase responses.

The acute phase response (APR) is a systemic first-line defense against challenges including infection, trauma, stress, and neoplasia. Alteration of acute phase protein (APP) levels in plasma is the most important change during acute phase response. C-reactive protein (CRP), which increases dramatically during inflammation onset, is an indicator of inflammation. To monitor the process of APR, we generated human CRP promoter-driven luciferase transgenic (hCRP-Luc) mice to quantify the hCRP promoter activation in vivo. The naïve female hCRP-Luc mice express low basal levels of liver bioluminescence, but the naïve male hCRP-Luc mice do not. Thus, female hCRP-Luc mice are suitable for monitoring the process of APR. The liver bioluminescence of female hCRP-Luc mice can be induced by several toll-like receptor (TLR) ligands. The expression of liver bioluminescence was highly sensitive to endotoxin stimulation in a dose-dependent manner. On-off-on bioluminescence response was noted in female hCRP-Luc mice upon two endotoxin stimulations one month apart. The LPS-induced bioluminescence of the female hCRP-Luc mice was IL-6-mediated and associated with APP alpha-1-acid glycoprotein expression. In conclusion, the female hCRP-Luc mouse is a non-invasive, sensitive and reusable reporter tool for APR.

Synthesis and characterization of di-nuclear bis(benzotriazole iminophenolate) cobalt complexes: catalysis for the copolymerization of carbon dioxide with epoxides.

A family of di-nuclear bis(benzotriazole iminophenolate) (BiIBTP) cobalt complexes containing diverse ancillary carboxylate derivatives have been synthesized and structurally characterized. The one-pot synthesis of the BiIBTP ligand precursor with cobalt perchlorate salt (2.0 equiv.) and carboxylic acid derivatives (2.0 or 5.0 equiv.) in the presence of triethylamine (5.0 equiv.) under refluxing methanolic solution generated bimetallic di-carboxylate Co(ii)/Co(ii) complexes [(C83CBiIBTP)Co2(O2CR)2] (R = C6H5 (1), C6F5 (2), 4-CF3-C6H4 (3), 4-OMe-C6H4 (4), CF3 (5)) in ≧65% yields. Interestingly, the Co(ii)/Co(iii) mixed-valence complex 6 resulted from the treatment of 1 with silver perchlorate (1.0 equiv.) as the oxidizing agent under an O2-atmosphere in 50% yield. The crystal structure of 6 reveals an ionic and di-nuclear benzoate species composed of a cationic moiety formulated as [(C83CBiIBTP)Co2(O2CC6H5)2]+ and a counterbalanced perchlorate anion, and both metal atoms are attributed to hexa-coordinated cobalt ions with varied coordination environments. Catalysis results of CO2/epoxide copolymerization indicated that complex 1 was more efficient than 2-6 where compound 6 was shown to be the least active. Co complex 1 incorporating benzoate coligands was demonstrated to effectively catalyze the CO2-copolymerization of cyclohexene oxide (CHO), 4-vinyl-1,2-cyclohexene oxide or cyclopentene oxide, producing the associated CO2-based polycarbonates with >99% carbonate repeated units under optimal conditions. Not only the controllable character of complex 1 for CO2/CHO copolymerization is enabled, but also 1 has been shown to catalyze such a copolymerization in the "immortal" manner. Using the same di-cobalt catalyst in combination with excess ratios of neopentyl glycol (up to 150 equiv.) as the chain transfer agent could give low molecular weight poly(cyclohexene carbonate) polyols with monomodal molecular weight distributions. This work offers the facilely prepared di-nuclear cobalt complexes as catalysts for the efficient catalysis of CO2-copolymerization.

B Cell Development sans B Cell Receptor Responsiveness Due to Unfolded Protein Response-Triggered Mef2c Protein Degradation.

BCR engagement leads to activation and clonal expansion of B cells. The I-A12% mutant mouse possesses a branch site point mutation in the H2-Aa gene that causes highly reduced I-Aa protein expression. As I-A is a heterodimer made up of I-Aa and I-Ab, reduced I-Aa results not only in reduced surface I-A expression but also in an excess of unpaired I-Ab. B cells that develop in I-A12% mice proliferated in response to LPS stimulation but failed to do so upon BCR stimulation. Developing I-A12% B cells were engaged in unfolded protein response due to an excess of unpaired I-Ab. BCR responsiveness was restored by transduced I-Aa expression and by BiP, the unfolded protein response sensor. Reducing the load of unpaired I-Ab also restored BCR responsiveness of I-A12% B cells. Mef2c protein, a transcription factor required for BCR-stimulated proliferation, was missing in I-A12% B cells, and that transduced Mef2c expression restored BCR responsiveness. Mef2c protein appeared in I-A12% B cells after addition of proteasome inhibitors. Mef2c degradation was mediated by Skp2 E3 ligase, and that knockdown of Skp2 mRNA in I-A12% B cells restored BCR responsiveness. Our results point to a generalized incompatibility between BCR responsiveness and increased Skp2 stability. They also imply the existence of regulatory mechanisms other than Ig gene rearrangement that govern Mef2c turnover in a specific, exquisite, and dynamic fashion.

Microporous 2D indium metal-organic frameworks for selective CO2 capture and their application in the catalytic CO2-cycloaddition of epoxides.

Four new 2D indium metal-organic frameworks (MOFs) (Me2NH2)[In(SBA)2] (1), (Me2NH2)[In(SBA)(BDC)] (2), (Me2NH2)[In(SBA)(BDC-NH2)] (3), and (NH4)3[In3Cl2(BPDC)5] (4), (H2SBA = 4,4'-sulfonyldibenzoic acid; H2BDC = 1,4-benzenedicarboxylic acid; H2BDC-NH2 = 2-amino-1,4-benzenedicarboxylic acid; H2BPDC = 4,4'-biphenyldicarboxylic acid) have been synthesized under solvothermal reaction conditions for compounds 1 to 3 and the DES (deep eutectic solvent) reaction has been attempted for compound 4. The structure of these MOFs has been determined by using single crystal X-ray diffraction study and all of theses four 2D monolayer framework with porous properties. The N2 gas sorption measurements indicated that Brunauer-Emmer-Teller (BET) and Langmuir surface areas of compound 1 are 207 and 301 m2 g-1, respectively, which is probably the first one having substantial gas uptake properties in the entire 2D In-MOF family to date. Furthermore, these new indium MOFs on the addition of n-Bu4NBr were active for the cycloaddition of CO2 and propylene oxide, generating propylene carbonates in high conversions under mild conditions. Particularly, the most active MOF 4 was found to efficiently couple CO2 with a series of terminal epoxides to give the corresponding cyclic organic carbonates with high selectivities.

Synthesis and characterization of trimetallic cobalt, zinc and nickel complexes containing amine-bis(benzotriazole phenolate) ligands: efficient catalysts for coupling of carbon dioxide with epoxides.

New trimetallic cobalt, nickel and zinc complexes 1-3 coordinated by amine-bis(benzotriazole phenolate) ligands and ancillary acetate groups have been developed for the use of CO2/epoxide coupling. All complexes were structurally characterized by single crystal X-ray crystallography; tri-Co complex 1 is the first solid-state example in which three different geometrical configurations exist in the same benzotriazole phenoxide metal complex. Tri-nuclear complexes 1 and 2 with cobalt and zinc metal centers were demonstrated to be very active catalysts for cycloaddition of cyclohexene oxide with CO2 in the presence of ammonium salt co-catalysts to give cis-cyclohexene carbonate under the conditions of 80 °C and 300 psi initial CO2 pressure. Particularly, tri-cobalt complex 1 was found to efficiently couple CO2 with epoxides showing broad substrate scope, producing the corresponding cyclic organic carbonates with good activities and high selectivities. This is a successful example of catalysis for cyclic carbonate synthesis using one cobalt(ii) complex as a homogeneous catalyst.

Glycolysis regulates the expansion of myeloid-derived suppressor cells in tumor-bearing hosts through prevention of ROS-mediated apoptosis.

Immunotherapy aiming to rescue or boost antitumor immunity is an emerging strategy for treatment of cancers. The efficacy of immunotherapy is strongly controlled by the immunological milieu of cancer patients. Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cell populations with immunosuppressive functions accumulating in individuals during tumor progression. The signaling mechanisms of MDSC activation have been well studied. However, there is little known about the metabolic status of MDSCs and the physiological role of their metabolic reprogramming. In this study, we discovered that myeloid cells upregulated their glycolytic genes when encountered with tumor-derived factors. MDSCs exhibited higher glycolytic rate than their normal cell compartment did, which contributed to the accumulation of the MDSCs in tumor-bearing hosts. Upregulation of glycolysis prevented excess reactive oxygen species (ROS) production by MDSCs, which protected MDSCs from apoptosis. Most importantly, we identified the glycolytic metabolite, phosphoenolpyruvate (PEP), as a vital antioxidant agent able to prevent excess ROS production and therefore contributed to the survival of MDSCs. These findings suggest that glycolytic metabolites have important roles in the modulation of fitness of MDSCs and could be potential targets for anti-MDSC strategy. Targeting MDSCs with analogs of specific glycolytic metabolites, for example, 2-phosphoglycerate or PEP may diminish the accumulation of MDSCs and reverse the immunosuppressive milieu in tumor-bearing individuals.

Low-Level MHC Class II Expression Leads to Suboptimal Th Cell Response, Increased Autoaggression, and Heightened Cytokine Inducibility.

The development and activation of MHC class II (MHC-II)-restricted CD4+ T cells are distinct immunological processes that are strictly MHC-II-dependent. To address their relative dependence on MHC-II, we established a novel ENU-induced mutant mouse on the C57BL/6 background, named I-A12%, with ∼8-fold reduced I-A expression on the surface of B cells, dendritic cells, cortical thymic epithelial cells, and medullary thymic epithelial cells. I-A100% and I-A12% mice are highly similar with respect to the numbers of double-positive thymocytes, CD4+CD8- T cells, regulatory T cells, CD4+ T cell marker expression, lifespan, and Th/regulatory T cell function. Despite the demonstration of functional intrathymic negative selection in I-A12% mice, transfer of I-A12% CD25-CD4+ T cells into RAG-knockout hosts revealed increased autoaggression activity against the liver. Compared to I-A100% mice, infection of I-A12% mice with graded doses of Listeria monotcytogenes or influenza virus revealed comparable and significantly reduced generation of Ag-specific CD4+ T cells at high and low infection doses, respectively. A significantly weakened Ag-specific recall cytokine production response was also found for I-A12% mice previously infected with a relative low dose of L. monocytogenes CD44hiCD4+ T cells from I-A100% and I-A12% mice previously infected with a relatively high L. monocytogenes dose displayed highly similar Ag-specific multicytokine production profiles. In contrast, polyclonal activation of endogenous memory-like I-A12% CD44hiCD4+ T cells revealed highly elevated production of multiple cytokines. Our results demonstrate that there exist distinct thresholds for different MHC-II-dependent immunological processes. The I-A12% mutant mouse model we describe in the present study is a valuable tool for investigations on the quantitative cause-effect relationship in MHC-II-dependent normal and autoimmune responses.