Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. While it is well-accepted that inflammation is central to NAFLD pathogenesis, the immune ...pathway(s) orchestrating disease progression are poorly defined. Notably, IL-17RA signaling, via IL-17A, plays an important role in obesity-driven NAFLD pathogenesis. However, the role of the IL-17F, another IL-17RA ligand, in NAFLD pathogenesis has not been examined. Further, the cell types expressing IL-17RA and producing IL-17RA ligands in the pathogenesis of NAFLD have not been defined. Here, IL-17RA-/-, IL-17A-/-, IL-17F-/- and wild-type (WT) mice were fed either standard chow diet or methionine and choline deficient diet (MCDD)--a diet known to induce steatosis and hepatic inflammation through beta-oxidation dysfunction--and hepatic inflammation and NAFLD progression were subsequently quantified. MCDD feeding augmented hepatic IL-17RA expression and significantly increased hepatic infiltration of macrophages and IL-17A and IL-17F producing CD4+ and CD8+ T cells in WT mice. In contrast, IL-17RA-/-, IL-17A-/-, and IL-17F-/- mice, despite increased steatosis, exhibited significant protection from hepatocellular damage compared to WT controls. Protection from hepatocellular damage correlated with decreased levels of hepatic T-cell and macrophage infiltration and decreased expression of inflammatory mediators associated with NAFLD. In sum, our results indicate that the IL-17 axis also plays a role in a MCDD-induced model of NAFLD pathogenesis. Further, we show for the first time that IL-17F, and not only IL-17A, plays an important role in NAFLD driven inflammation.
Prions are proteins that adopt alternative conformations that become self-propagating; the PrPScprion causes the rare human disorder Creutzfeldt–Jakob disease (CJD). We report here that multiple ...system atrophy (MSA) is caused by a different human prion composed of the α-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein. To determine whether human α-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human α-synuclein fused to yellow fluorescent protein (α-syn140*A53T–YFP) and TgM83+/−mice expressing α-synuclein (A53T). The TgM83+/−mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83+/+mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83+/−mice after incubation periods of ∼120 d, which was accompanied by deposition of α-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of α-syn*A53T–YFP in cultured cells, whereas none of six Parkinson’s disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of α-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83+/+mice. Remarkably, α-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.
Obesity is a primary risk factor for the development of non-alcoholic fatty liver disease (NAFLD). NAFLD, the most common chronic liver disease in the world, represents a spectrum of disorders that ...range from steatosis (NAFL) to steatohepatitis (NASH) to cirrhosis. It is anticipated that NAFLD will soon surpass chronic hepatitis C infection as the leading cause for needing liver transplantation. Despite its clinical and public health significance no specific therapies are available. Although the etiology of NAFLD is multifactorial and remains largely enigmatic, it is well accepted that inflammation is a central component of NAFLD pathogenesis. Despite the significance, critical immune mediators, loci of immune activation, the immune signaling pathways and the mechanism(s) underlying disease progression remain incompletely understood. Recent findings have focused on the role of Interleukin 17 (IL-17) family of proinflammatory cytokines in obesity and pathogenesis of obesity-associated sequelae. Notably, obesity favors a Th17 bias and is associated with increased IL-17A expression in both humans and mice. Further, in mice, IL-17 axis has been implicated in regulation of both obesity and NAFLD pathogenesis. However, despite these recent advances several important questions require further evaluation including: the relevant cellular source of IL-17A production; the critical IL- 17RA-expressing cell type; the critical liver infiltrating immune cells; and the underlying cellular effector mechanisms. Addressing these questions may aid in the identification and development of novel therapeutic targets for prevention of inflammation- driven NAFLD progression.
Nonalcoholic fatty liver disease (NAFLD), a common prelude to cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide. Defining the molecular mechanisms underlying ...the pathogenesis of NAFLD has been hampered by a lack of animal models that closely recapitulate the severe end of the disease spectrum in humans, including bridging hepatic fibrosis. Here we demonstrate that a novel experimental model employing thermoneutral housing, as opposed to standard housing, resulted in lower stress-driven production of corticosterone, augmented mouse proinflammatory immune responses and markedly exacerbated high-fat diet (HFD)-induced NAFLD pathogenesis. Disease exacerbation at thermoneutrality was conserved across multiple mouse strains and was associated with augmented intestinal permeability, an altered microbiome and activation of inflammatory pathways that are associated with the disease in humans. Depletion of Gram-negative microbiota, hematopoietic cell deletion of Toll-like receptor 4 (TLR4) and inactivation of the IL-17 axis resulted in altered immune responsiveness and protection from thermoneutral-housing-driven NAFLD amplification. Finally, female mice, typically resistant to HFD-induced obesity and NAFLD, develop full disease characteristics at thermoneutrality. Thus, thermoneutral housing provides a sex-independent model of exacerbated NAFLD in mice and represents a novel approach for interrogation of the cellular and molecular mechanisms underlying disease pathogenesis.
Emerging evidence suggests a key contribution to non-alcoholic fatty liver disease (NAFLD) pathogenesis by Th17 cells. The pathogenic characteristics and mechanisms of hepatic Th17 cells, however, ...remain unknown. Here, we uncover and characterize a distinct population of inflammatory hepatic CXCR3+Th17 (ihTh17) cells sufficient to exacerbate NAFLD pathogenesis. Hepatic ihTh17 cell accrual was dependent on the liver microenvironment and CXCR3 axis activation. Mechanistically, the pathogenic potential of ihTh17 cells correlated with increased chromatin accessibility, glycolytic output, and concomitant production of IL-17A, IFNγ, and TNFα. Modulation of glycolysis using 2-DG or cell-specific PKM2 deletion was sufficient to reverse ihTh17-centric inflammatory vigor and NAFLD severity. Importantly, ihTh17 cell characteristics, CXCR3 axis activation, and hepatic expression of glycolytic genes were conserved in human NAFLD. Together, our data show that the steatotic liver microenvironment regulates Th17 cell accrual, metabolism, and competence toward an ihTh17 fate. Modulation of these pathways holds potential for development of novel therapeutic strategies for NAFLD.
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•Obesity promotes accrual of a unique inflammatory hepatic Th17 (ihTh17) cell subset•ihTh17 cells are sufficient to exacerbate NAFLD progression•The activation of CXCR3 axis in steatotic liver promotes ihTh17 cell accrual•Glycolysis-associated PKM2 activity shapes the ihTh17 inflammatory potential
Non-alcoholic fatty liver disease (NAFLD) is associated with increased inflammation. Moreno-Fernandez et al. now show that the steatotic liver microenvironment gives rise to a distinct inflammatory hepatic Th17 (ihTh17) cell subset, which preferentially utilizes the glycolytic pathway to fuel tissue inflammation and promote NAFLD progression.
Inflammation plays a central pathogenic role in the pernicious metabolic and end‐organ sequelae of obesity. Among these sequelae, nonalcoholic fatty liver disease (NAFLD) has become the most common ...chronic liver disease in the developed world. The twinned observations that obesity is associated with increased activation of the interleukin (IL)‐17 axis and that this axis can regulate liver damage in diverse contexts prompted us to address the role of IL‐17RA signaling in the progression of NAFLD. We further examined whether microbe‐driven IL‐17A regulated NAFLD development and progression. We show here that IL‐17RA−/− mice respond to high‐fat diet stress with significantly greater weight gain, visceral adiposity, and hepatic steatosis than wild‐type controls. However, obesity‐driven lipid accumulation was uncoupled from its end‐organ consequences in IL‐17RA−/− mice, which exhibited decreased steatohepatitis, nicotinamide adenine dinucleotide phosphate (NADPH)‐oxidase enzyme expression, and hepatocellular damage. Neutralization of IL‐17A significantly reduced obesity‐driven hepatocellular damage in wild‐type mice. Further, colonization of mice with segmented filamentous bacteria (SFB), a commensal that induces IL‐17A production, exacerbated obesity‐induced hepatocellular damage. In contrast, SFB depletion protected from obesity‐induced hepatocellular damage. Conclusion: These data indicate that obesity‐driven activation of the IL‐17 axis is central to the development and progression of NAFLD to steatohepatitis and identify the IL‐17 pathway as a novel therapeutic target in this condition. (Hepatology 2014;59:1830–1839)
The inflammatory Bowel diseases (IBDs) are a chronic, relapsing inflammatory diseases of the gastrointestinal tract with heterogeneous behavior and prognosis. The introduction of biological therapies ...including anti-TNF, anti-IL-12/23, and anti-integrins, has revolutionized the treatment of IBD, but these drugs are not universally effective. Due to the complex molecular structures of biologics, they are uniformly immunogenic. New discoveries concerning the underlying mechanisms involved in the pathogenesis of IBD have allowed for progress in the development of new treatment options. The advantage of small molecules (SMs) over biological therapies includes their lack of immunogenicity, short half-life, oral administration, and low manufacturing cost. Among these, the Janus Kinases (JAKs) inhibition has emerged as a novel strategy to modulate downstream cytokine signaling during immune-mediated diseases. These drugs target various cytokine signaling pathways that participate in the pathogenesis of IBD. Tofacitinib, a JAK inhibitor targeting predominantly JAK1 and JAK3, has been approved for the treatment of ulcerative colitis (UC), and there are other specific JAK inhibitors under development that may be effective in Crohn's. Similarly, the traffic of lymphocytes can now be targeted by another SM. Sphingosine-1-phosphate receptor (S1PR) agonism is a novel strategy that acts, in part, by interfering with lymphocyte recirculation, through blockade of lymphocyte egress from lymph nodes. S1PR agonists are being studied in IBD and other immune-mediated disorders. This review will focus on SM drugs approved and under development, including JAK inhibitors (tofacitinib, filgotinib, upadacitinib, peficitinib) and S1PR agonists (KRP-203, fingolimod, ozanimod, etrasimod, amiselimod), and their mechanism of action.
Innate lymphoid cells (ILCs) are a lymphocyte population that is mostly resident at mucosal surfaces. They help to induce an appropriate immune response to the microbiome at homeostasis. In healthy ...people, the mucosal immune system works symbiotically with organisms that make up the microbiota. ILCs play a critical role in orchestrating this balance, as they can both influence and in turn be influenced by the microbiome. ILCs also are important regulators of the early response to infections by diverse types of pathogenic microbes at mucosal barriers. Their rapid responses initiate inflammatory programs, production of antimicrobial products and repair processes. This review will focus on the role of ILCs in response to the microbiota and to microbial infections of the lung and intestine.
We report new polarimetric and photometric maps of the massive star-forming region OMC-1 using the HAWC+ instrument on the Stratospheric Observatory for Infrared Astronomy. We present continuum ...polarimetric and photometric measurements of this region at 53, 89, 154, and 214 m at angular resolutions of 5″, 8″, 14″, and 19″ for the four bands, respectively. The photometric maps enable the computation of improved spectral energy distributions for the region. We find that at the longer wavelengths, the inferred magnetic field configuration matches the "hourglass" configuration seen in previous studies, indicating magnetically regulated star formation. The field morphology differs at the shorter wavelengths. The magnetic field inferred at these wavelengths traces the bipolar structure of the explosive Becklin-Neugebauer/Kleinman-Low outflow emerging from OMC-1 behind the Orion Nebula. Using statistical methods to estimate the field strength in the region, we find that the explosion dominates the magnetic field near the center of the feature. Farther out, the magnetic field is close to energetic equilibrium with the ejecta and may be providing confinement to the explosion. The correlation between polarization fraction and the local polarization angle dispersion indicates that the depolarization as a function of unpolarized intensity is a result of intrinsic field geometry as opposed to decreases in grain alignment efficiency in denser regions.
Caffeine intake in a convenience sample of U.S. college students (N = 1248) was surveyed at five geographically-dispersed United States (U.S.) universities.
Intake from coffee, tea, soft drinks, ...energy drinks, gums, and medications was assessed. Associations between caffeine intake and demographic variables including sex, age, race/ethnicity, family income, general health, exercise, weight variables and tobacco use were examined. Reasons for use of caffeine-containing products were assessed.
Caffeine, in any form, was consumed by 92% of students in the past year. Mean daily caffeine consumption for all students, including non-consumers, was 159 mg/d with a mean intake of 173 mg/d among caffeine users. Coffee was the main source of caffeine intake in male (120 mg/d) and female (111 mg/d) consumers. Male and female students consumed 53 vs. 30 mg/d of caffeine in energy drinks, respectively, and 28% consumed energy drinks with alcohol on at least one occasion. Students provided multiple reasons for caffeine use including: to feel awake (79%); enjoy the taste (68%); the social aspects of consumption (39%); improve concentration (31%); increase physical energy (27%); improve mood (18%); and alleviate stress (9%).
As in the general U.S. population, coffee is the primary source of caffeine intake among the college students surveyed. Energy drinks provide less than half of total daily caffeine intake but more than among the general population. Students, especially women, consume somewhat more caffeine than the general population of individuals aged 19–30 y but less than individuals aged 31–50 y.
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