Metformin Modulates T Cell Function and Alleviates Liver Injury Through Bioenergetic Regulation in Viral Hepatitis.

Metformin is not only the first-line medication for the treatment of type 2 diabetes, but it is also effective as an anti-inflammatory, anti-oxidative and anti-tumor agent. However, the effect of metformin during viral hepatitis remains elusive. Using an adenovirus (Ad)-induced viral hepatitis mouse model, we found that metformin treatment significantly attenuated liver injury, with reduced serum aspartate transaminase (AST) and alanine transaminase (ALT) levels and liver histological changes, presumably via decreased effector T cell responses. We then demonstrated that metformin reduced mTORC1 activity in T cells from infected mice, as evidenced by decreased phosphorylation of ribosome protein S6 (p-S6). The inhibitory effects on the mTORC1 signaling by metformin was dependent on the tuberous sclerosis complex 1 (TSC1). Mechanistically, metformin treatment modulated the phosphorylation of dynamin-related protein 1 (Drp-1) and mitochondrial fission 1 protein (FIS1), resulting in increased mass in effector T cells. Moreover, metformin treatment promoted mitochondrial superoxide production, which can inhibit excessive T cell activation in viral hepatitis. Together, our results revealed a protective role and therapeutic potential of metformin against liver injury in acute viral hepatitis via modulating effector T cell activation via regulating the mTORC1 pathway and mitochondrial functions.

Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity.

Innate lymphoid cells (ILCs) and CD4+ T cells produce IL-22, which is critical for intestinal immunity. The microbiota is central to IL-22 production in the intestines; however, the factors that regulate IL-22 production by CD4+ T cells and ILCs are not clear. Here, we show that microbiota-derived short-chain fatty acids (SCFAs) promote IL-22 production by CD4+ T cells and ILCs through G-protein receptor 41 (GPR41) and inhibiting histone deacetylase (HDAC). SCFAs upregulate IL-22 production by promoting aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor 1α (HIF1α) expression, which are differentially regulated by mTOR and Stat3. HIF1α binds directly to the Il22 promoter, and SCFAs increase HIF1α binding to the Il22 promoter through histone modification. SCFA supplementation enhances IL-22 production, which protects intestines from inflammation. SCFAs promote human CD4+ T cell IL-22 production. These findings establish the roles of SCFAs in inducing IL-22 production in CD4+ T cells and ILCs to maintain intestinal homeostasis.

Retinoic Acid Modulates Hyperactive T Cell Responses and Protects Vitamin A-Deficient Mice against Persistent Lymphocytic Choriomeningitis Virus Infection.

Vitamin A deficiency (VAD) is a major public health problem and is associated with increased host susceptibility to infection; however, how VAD influences viral infection remains unclear. Using a persistent lymphocytic choriomeningitis virus infection model, we showed in this study that although VAD did not alter innate type I IFN production, infected VAD mice had hyperactive, virus-specific T cell responses at both the acute and contraction stages, showing significantly decreased PD-1 but increased cytokine (IFN-γ, TNF-α, and IL-2) expression by T cells. Compared with control mice, VAD mice displayed excessive inflammation and more severe liver pathology, with increased death during persistent infection. Of note, supplements of all-trans retinoic acid (RA), one of the important metabolites of vitamin A, downregulated hyperactive T cell responses and rescued the persistently infected VAD mice. By using adoptive transfer of splenocytes, we found that the environmental vitamin A or its metabolites acted as rheostats modulating antiviral T cells. The analyses of T cell transcriptional factors and signaling pathways revealed the possible mechanisms of RA, as its supplements inhibited the abundance of NFATc1 (NFAT 1), a key regulator for T cell activation. Also, following CD3/CD28 cross-linking stimulation, RA negatively regulated the TCR-proximal signaling in T cells, via decreased phosphorylation of Zap70 and its downstream signals, including phosphorylated AKT, p38, ERK, and S6, respectively. Together, our data reveal VAD-mediated alterations in antiviral T cell responses and highlight the potential utility of RA for modulating excessive immune responses and tissue injury in infectious diseases.

[Raw Materials and End Treatment-based Emission Factors for Volatile Organic Compounds (VOCs) from Typical Solvent Use Sources].

A database of refined raw materials and end treatment-based VOCs emission factors for typical solvent use sources was developed for the Pearl River Delta. For this, the impact of composition and the content of raw materials, production process, and comprehensive end treatment on the emission of VOCs was analyzed. The solvent use sources included printing, furniture manufacturing, and electronic component and equipment manufacturing. The results showed that the main VOCs in the raw materials used in printing were ethyl acetate, propyl acetate, isopropanol, propanol, and ethanol, which contributed 60%-80% to the total amount of VOCs. Ethyl acetate and butyl acetate were the main oxygenated VOCs (OVOCs) from the raw materials used in furniture manufacturing, contributing 45%-65% of the total. The main VOCs from the raw materials used in electronic component and equipment manufacturing were OVOCs such as alcohols, ethers and phenols, BTEX, and halohydrocarbons. The uncontrolled and controlled emission factors for VOCs from printing were 415.2 kg·t-1 and 184.3 kg·t-1, respectively. Of these, solvent-based raw materials accounted for 704.9 kg·t-1 and 200.1 kg·t-1, water-based raw materials accounted for 325.6 kg·t-1 and 230.3 kg·t-1, UV raw materials accounted for 197.0 kg·t-1 and 129.0 kg·t-1, and plant-based raw materials accounted for 89.0 kg·t-1 and 89.0 kg·t-1, respectively. The uncontrolled and controlled emission factors for VOCs from furniture manufacturing were 379.0 kg·t-1 and 290.2 kg·t-1, respectively. Of these, solvent-based raw materials accounted for 603.0 kg·t-1 and 448.5 kg·t-1, water-based raw materials accounted for 80.0 kg·t-1 and 80.0 kg·t-1, and powder raw materials accounted for 230.0 kg·t-1 and 184.0 kg·t-1, respectively. In electronic component and equipment manufacturing, the uncontrolled and controlled emission factors (unit:kg·million-1) for VOCs from AC ceramic capacitors, CC ceramic capacitors, varistors, and aluminum electrolytic capacitors were 59.7 and 40.8, 394.1 and 269.6, 282.4 and 193.2, and 1.2 and 1.0, respectively. The uncontrolled and controlled emission factors for VOCs from the manufacturing of continuous terminals, enameled wire, and printed circuit boards were 56.3 kg·t-1 and 42.8 kg·t-1, 87.2 kg·t-1 and 28.3 kg·t-1, and 26.4 kg·(100 m2)-1 and 11.6 kg·(100 m2)-1, respectively.

Redox regulation of hepatic NLRP3 inflammasome activation and immune dysregulation in trichloroethene-mediated autoimmunity.

Trichloroethene (TCE) exposure is associated with the development of various autoimmune diseases (ADs), including autoimmune hepatitis (AIH) and systemic lupus erythematosus (SLE), potentially through the generation of excessive reactive oxygen and nitrogen species (RONS; oxidative stress). However, the mechanisms by which oxidative stress contributes to these TCE-mediated ADs are not fully understood, and are the focus of current investigation. Female MRL+/+ mice were treated with TCE along with or without antioxidant N-acetylcysteine (NAC) for 6 weeks (TCE, 10 mmol/kg, i. p., every 4th day; NAC, 250 mg/kg/day via drinking water). TCE-treated mice had elevated antinuclear antibodies (ANA) and 4-hydroxynonenal (HNE)-specific circulating immune complexes, suggesting the association of TCE-induced oxidative stress with autoimmune response. In addition, TCE exposure led to prominent lobular inflammation with sinusoid dilation, increased sinusoidal cellularity and increased staining for proliferating cell nuclear antigen (PCNA), confirming inflammatory and hepatocellular cell proliferation. Importantly, TCE exposure resulted in the activation of hepatic inflammasome (NLRP3 and caspase-1) and up-regulation of pro-inflammatory cytokine IL-1ß, and these changes were attenuated by NAC supplementation. TCE treatment also led to dysregulation of hepatic immune response as evident from markedly increased hepatic lymphocyte infiltration (especially B cells) and imbalance between Tregs (decreased) and Th17 cells (increased). Interestingly, TCE-mediated dysregulation of various hepatic and splenic immune cells was also effectively attenuated by NAC. Taken together, our findings provide evidence for TCE-mediated inflammasome activation, infiltration of various immune cells, and skewed balance of Treg and Th17 cells in the liver. The attenuation of TCE-mediated hepatic inflammasome activation and immune responses by NAC further supports a critical role of oxidative stress in TCE-mediated inflammation and autoimmunity. These novel findings could help in designing therapeutic strategies for such ADs.