While TGF-β signaling is essential for microglial function, the cellular source of TGF-β1 ligand and its spatial regulation remains unclear in the adult CNS. Our data supports that microglia but not astrocytes or neurons are the primary producers of TGF-β1 ligands needed for microglial homeostasis. Microglia-Tgfb1 KO leads to the activation of microglia featuring a dyshomeostatic transcriptome that resembles disease-associated, injury-associated, and aged microglia, suggesting microglial self-produced TGF-β1 ligands are important in the adult CNS.
View Article and Find Full Text PDFJ Pediatr Gastroenterol Nutr
July 2021
To investigate the effect of high fructose diet on ultrastructure and content of hepatic mitochondria, we randomized 6-8 weeks old male C57Bl6/J mice to ad lib chow or high-fat-high-fructose (HF2) diet for 32 weeks. HF2-fed mice gained more weight, had higher plasma alanine aminotransferase, and fasting glucose levels and increased hepatic triglyceride content at all time points compared to chow-fed mice. HF2-fed mice had lower mitochondrial to nuclear DNA ratio compared to chow-fed mice.
View Article and Find Full Text PDFArgonaute 2 (Ago2) is the main component of the RNA-induced silencing complex. We recently showed that liver-specific Ago2-deficiency in mice (L-Ago2 knockout [KO] mice) enhances mitochondrial oxidation and alleviates obesity-associated pathophysiology. However, the precise mechanisms behind the role of hepatic Ago2 in regulating the mitochondrial oxidation associated with glucose metabolism are still unclear.
View Article and Find Full Text PDFAm J Physiol Gastrointest Liver Physiol
September 2020
Vertical sleeve gastrectomy (VSG) is the best current therapy for remission of obesity and its co-morbidities. It is understood to alter the enterohepatic circulation of bile acids in vivo. Fibroblast growth factor 19 (FGF19) in human and its murine orthologue Fgf15 plays a pivotal role in this bile acid driven enterohepatic signaling.
View Article and Find Full Text PDFSugar-sweetened beverage consumption is a known independent risk factor for nonalcoholic steatohepatitis (NASH). Non-caloric sweeteners (NCS) are food additives providing sweetness without calories and are considered safe and/or not metabolized by the liver. The potential role of newer NCS in the regulation of NASH, however, remain unknown.
View Article and Find Full Text PDFObjective: Vertical sleeve gastrectomy (VSG) results in weight loss and increased bile acids (BA) and fibroblast growth factor 19 (FGF19) levels. FGF21 shares essential cofactors with FGF19, but its physiology early post-VSG has not been assessed.
Methods: Ten adolescents (17.
Bariatric surgery is the most effective and durable treatment option for obesity today. More importantly, beyond weight loss, bariatric procedures have many advantageous metabolic effects including reversal of obesity-related liver disease--nonalcoholic steatohepatitis (NASH). NASH is an important comorbidity of obesity given that it is a precursor to the development of liver cirrhosis that may necessitate liver transplantation in the long run.
View Article and Find Full Text PDFObjective: Bile acids (BA) are elevated after vertical sleeve gastrectomy (VSG) and farnesoid-X-receptor (FXR) is critical to the success of murine VSG. BA downregulate hepatic lipogenesis by activating the FXR-small heterodimer partner (SHP) pathway. The role of SHP in fatty liver disease improvement after VSG was tested.
View Article and Find Full Text PDFUp to a third of the world's population is infected with Toxoplasma gondii. Natural infection in humans can be life threatening during pregnancy and in immunocompromised individuals. Toll-like receptor (TLR) 11 is the mouse innate sensor that recognizes T.
View Article and Find Full Text PDFCerebral malaria is caused by infection with Plasmodium falciparum and can lead to severe neurological manifestations and predominantly affects sub-Saharan African children. The pathogenesis of this disease involves unbalanced over-production of pro-inflammatory cytokines. It is clear that signaling though IL-12 receptor is a critical step for development of cerebral malaria, IL-12 genetic deficiency failed to show the same effect, suggesting that there is redundancy among the soluble mediators which leads to immunopathology and death.
View Article and Find Full Text PDFPattern recognition receptors and receptors for pro-inflammatory cytokines provide critical signals to drive the development of protective immunity to infection. Therefore, counter-regulatory pathways are required to ensure that overwhelming inflammation harm host tissues. Previously, we showed that lipoxins modulate immune response during infection, restraining inflammation during infectious diseases in an Aryl hydrocarbon receptor (AhR)/suppressors of cytokine signaling (SOCS)2-dependent-manner.
View Article and Find Full Text PDFDendritic cells (DCs) play a vital role in initiating robust immunity against pathogens as well as maintaining immunological tolerance to self antigens. However, the intracellular signaling networks that program DCs to become tolerogenic remain unknown. We report here that the Wnt-beta-catenin signaling in intestinal dendritic cells regulates the balance between inflammatory versus regulatory responses in the gut.
View Article and Find Full Text PDFBacterial flagellin is a target of innate and adaptive immune responses during Salmonella infection. Intravenous injection of Salmonella flagellin into C57BL/6 mice induced rapid IL-6 production and increased expression of activation markers by splenic dendritic cells. CD11b(+), CD8alpha(+), and plasmacytoid dendritic cells each increased expression of CD86 and CD40 in response to flagellin stimulation, although CD11b(+) dendritic cells were more sensitive than the other subsets.
View Article and Find Full Text PDFProduction of IFN-gamma by CD4 T cells is generally thought to be mediated by TCR triggering, however, Ag-nonspecific activation of effector CD8 T cells has been reported in infection models. In this study, we demonstrate that Ag-experienced CD4 T cells in the spleen of Salmonella-infected mice acquire the capacity to rapidly secrete IFN-gamma in response to stimulation with bacterial lysate or LPS. This innate responsiveness of T cells was transient and most apparent during, and immediately following, active Salmonella infection.
View Article and Find Full Text PDFT cell activation by dendritic cells (DCs) is critical to the initiation of adaptive immune responses and protection against pathogens. Here, we demonstrate that a specialized DC subset in Peyer's patches (PPs) mediates the rapid activation of pathogen specific T cells. This DC subset is characterized by the expression of the chemokine receptor CCR6 and is found only in PPs.
View Article and Find Full Text PDFBacterial flagellins are important components of the motility apparatus used by many microbial pathogens. These proteins are also targets of the innate and adaptive immune response of the host during infection and autoimmune disease. Flagellin interacts with TLR-5 and leads to the generation of a pro-inflammatory response and activation of host dendritic cells in vivo.
View Article and Find Full Text PDFImmunol Lett
May 2004
Typhoid fever remains a serious public health problem. We have developed a vaccine from Salmonella enterica serovar typhi (S. typhi) outer-membrane proteins (OMPs) known as porins.
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