Non-hematopoietic IL-4Rα expression contributes to fructose-driven obesity and metabolic sequelae.

OBJECTIVE: The risks of excess sugar intake in addition to high-fat diet consumption on immunopathogenesis of obesity-associated metabolic diseases are poorly defined. Interleukin-4 (IL-4) and IL-13 signaling via IL-4Rα regulates adipose tissue lipolysis, insulin sensitivity, and liver fibrosis in obesity. However, the contribution of IL-4Rα to sugar rich diet-driven obesity and metabolic sequelae remains unknown. METHODS: WT, IL-4Rα-deficient (IL-4Rα-/-) and STAT6-deficient mice (STAT6-/-) male mice were fed low-fat chow, high fat (HF) or HF plus high carbohydrate (HC/fructose) diet (HF + HC). Analysis included quantification of: (i) body weight, adiposity, energy expenditure, fructose metabolism, fatty acid oxidation/synthesis, glucose dysmetabolism and hepatocellular damage; (ii) the contribution of the hematopoietic or non-hematopoietic IL-4Rα expression; and (iii) the relevance of IL-4Rα downstream canonical STAT6 signaling pathway in this setting. RESULTS: We show that IL-4Rα regulated HF + HC diet-driven weight gain, whole body adiposity, adipose tissue inflammatory gene expression, energy expenditure, locomotor activity, glucose metabolism, hepatic steatosis, hepatic inflammatory gene expression and hepatocellular damage. These effects were potentially, and in part, dependent on non-hematopoietic IL-4Rα expression but were independent of direct STAT6 activation. Mechanistically, hepatic ketohexokinase-A and C expression was dependent on IL-4Rα, as it was reduced in IL-4Rα-deficient mice. KHK activity was also affected by HF + HC dietary challenge. Further, reduced expression/activity of KHK in IL-4Rα mice had a significant effect on fatty acid oxidation and fatty acid synthesis pathways. CONCLUSION: Our findings highlight potential contribution of non-hematopoietic IL-4Rα activation of a non-canonical signaling pathway that regulates the HF + HC diet-driven induction of obesity and severity of obesity-associated sequelae.

Biased Sampling and Causal Estimation of Health-Related Information: Laboratory-Based Experimental Research.

BACKGROUND: The internet is a relevant source of health-related information. The huge amount of information available on the internet forces users to engage in an active process of information selection. Previous research conducted in the field of experimental psychology showed that information selection itself may promote the development of erroneous beliefs, even if the information collected does not. OBJECTIVE: The aim of this study was to assess the relationship between information searching strategy (ie, which cues are used to guide information retrieval) and causal inferences about health while controlling for the effect of additional information features. METHODS: We adapted a standard laboratory task that has previously been used in research on contingency learning to mimic an information searching situation. Participants (N=193) were asked to gather information to determine whether a fictitious drug caused an allergic reaction. They collected individual pieces of evidence in order to support or reject the causal relationship between the two events by inspecting individual cases in which the drug was or was not used or in which the allergic reaction appeared or not. Thus, one group (cause group, n=105) was allowed to sample information based on the potential cause, whereas a second group (effect group, n=88) was allowed to sample information based on the effect. Although participants could select which medical records they wanted to check-cases in which the medicine was used or not (in the cause group) or cases in which the effect appeared or not (in the effect group)-they all received similar evidence that indicated the absence of a causal link between the drug and the reaction. After observing 40 cases, they estimated the drug-allergic reaction causal relationship. RESULTS: Participants used different strategies for collecting information. In some cases, participants displayed a biased sampling strategy compatible with positive testing, that is, they required a high proportion of evidence in which the drug was administered (in the cause group) or in which the allergic reaction appeared (in the effect group). Biased strategies produced an overrepresentation of certain pieces of evidence at the detriment of the representation of others, which was associated with the accuracy of causal inferences. Thus, how the information was collected (sampling strategy) demonstrated a significant effect on causal inferences (F1,185=32.53, P<.001, η2p=0.15) suggesting that inferences of the causal relationship between events are related to how the information is gathered. CONCLUSIONS: Mistaken beliefs about health may arise from accurate pieces of information partially because of the way in which information is collected. Patient or person autonomy in gathering health information through the internet, for instance, may contribute to the development of false beliefs from accurate pieces of information because search strategies can be biased.

Short-term high-fat diet feeding protects from the development of experimental allergic asthma in mice.

BACKGROUND: A close association between obesity and asthma has been described. The nature of this association remains elusive, especially with respect to allergic asthma. Controversial findings exist regarding the impact of short-term high-fat diet (HFD) feeding on the development of allergic asthma. OBJECTIVE: To delineate the impact of short-term HFD feeding on the development of experimental allergic asthma. METHODS: Female C57BL/6JRJ mice were fed with a short-term HFD or chow diet (CD) for 12 weeks. Allergic asthma was induced by intraperitoneal OVA/alum sensitization followed by repeated OVA airway challenges. We determined airway hyperresponsiveness (AHR) and pulmonary inflammation by histologic and flow cytometric analysis of immune cells. Furthermore, we assessed the impact of HFD on dendritic cell (DC)-mediated activation of T cells. RESULTS: Female mice showed a mild increase in body weight accompanied by mild metabolic alterations. Upon OVA challenge, CD-fed mice developed strong AHR and airway inflammation, which were markedly reduced in HFD-fed mice. Mucus production was similar in both treatment groups. OVA-induced increases in DC and CD4+ T-cell recruitment to the lungs were significantly attenuated in HFD-fed mice. MHC-II expression and CD40 expression in pulmonary CD11b+ DCs were markedly lower in HFD-fed compared to CD-fed mice, which was associated in vivo with a decreased T helper (Th) 1/17 differentiation and Treg formation without impacting Th2 differentiation. CONCLUSIONS/CLINICAL RELEVANCE: These findings suggest that short-term HFD feeding attenuates the development of AHR, airway inflammation, pulmonary DC recruitment and MHC-II/CD40 expression leading to diminished Th1/17 but unchanged Th2 differentiation. Thus, short-term HFD feeding and associated metabolic alterations may have protective effects in allergic asthma development.

High density lipoproteins selectively promote the survival of human regulatory T cells.

HDLs appear to affect regulatory T cell (Treg) homeostasis, as suggested by the increased Treg counts in HDL-treated mice and by the positive correlation between Treg frequency and HDL-cholesterol levels in statin-treated healthy adults. However, the underlying mechanisms remain unclear. Herein, we show that HDLs, not LDLs, significantly decreased the apoptosis of human Tregs in vitro, whereas they did not alter naïve or memory CD4+ T cell survival. Similarly, oleic acid bound to serum albumin increased Treg survival. Tregs bound and internalized high amounts of HDL compared with other subsets, which might arise from the higher expression of the scavenger receptor class B type I by Tregs; accordingly, blocking this receptor hindered HDL-mediated Treg survival. Mechanistically, we showed that HDL increased Treg ATP concentration and mitochondrial activity, enhancing basal respiration, maximal respiration, and spare respiratory capacity. Blockade of FA oxidation by etoxomir abolished the HDL-mediated enhanced survival and mitochondrial activity. Our findings thus suggest that Tregs can specifically internalize HDLs from their microenvironment and use them as an energy source. Furthermore, a novel implication of our data is that enhanced Treg survival may contribute to HDLs' anti-inflammatory properties.

Neonatal regulatory T cells have reduced capacity to suppress dendritic cell function.

Regulatory T cells (Treg cells) limit contact between dendritic cells (DCs) and conventional T cells (Tcons), decreasing the formation of aggregates as well as down-modulating the expression of co-stimulatory molecules by DCs, thus decreasing DC immunogenicity and abrogating T-cell activation. Despite the importance of this Treg-cell function, the capacity of Treg cells from term and preterm neonates to suppress DCs, and the suppressive mechanisms they use, are still undefined. We found that, relative to adult Treg cells, activated Treg cells from human neonates expressed lower FOXP3 and CTLA-4, but contained higher levels of cAMP. We developed an in vitro model in which Treg function was measured at a physiological ratio of 1 Treg for 10 Tcon and 1 monocyte-derived DC, as Treg target. Term and preterm Treg cells failed to suppress the formation of DC-Tcon aggregates, in contrast to naïve and memory Treg cells from adults. However, neonatal Treg cells diminished DC and Tcon activation as well as actin polymerization at the immunological synapses. In addition, CTLA-4 and cAMP were the main suppressive molecules used by neonatal Treg. Altogether, both preterm and term neonatal Treg cells appear less functional than adult Treg cells, and this defect is consistent with the general impairment of CD4 cell function in newborns.

Presurgery health influences outcomes following vertical sleeve gastrectomy in adolescents.

OBJECTIVE: Weight loss following vertical sleeve gastrectomy (VSG) in youth can range from 10% to 50%. We examined whether there are differences in demographic or metabolic parameters before VSG in youth who achieve above-average weight loss (AAWL) versus below-average weight loss (BAWL) at 1 year post VSG and if youth with BAWL still achieve metabolic health improvements at 1 year post VSG. METHODS: Demographic, anthropometric, and clinical lab data were collected before VSG and at 1, 3, 6, and 12 months after VSG. RESULTS: Forty-three youth with a mean age of 16.9 (SD 1.7) years before VSG were studied; 70% were female, 19% non-Hispanic Black, 58% non-Hispanic White, and 23% mixed/other race. Mean baseline BMI was 51.1 (SD 10.5) kg/m2. Average weight loss was 25.8%. The AAWL group lost 18.6 kg/m2 (35.3%) versus the BAWL group, who lost 8.8 kg/m2 (17.5%). BMI, age, race, sex, and socioeconomic status at baseline were similar between AAWL and BAWL groups; however, the BAWL group had a higher frequency of pre-VSG dysglycemia, steatotic liver disease, and dyslipidemia. At 1 year post VSG, fewer youth in the BAWL group achieved ideal health parameters, and they had less resolution of comorbidities. CONCLUSIONS: The presence of comorbidities before VSG is associated with less weight loss and reduced resolution of metabolic conditions at 1 year post VSG.

Patient-derived colon epithelial organoids reveal lipid-related metabolic dysfunction in pediatric ulcerative colitis.

Ulcerative colitis (UC) is associated with epithelial metabolic derangements which exacerbate gut inflammation. Patient-derived organoids recapitulate complexities of the parent tissue in health and disease; however, whether colon organoids (colonoids) model the metabolic impairments in the pediatric UC epithelium is unclear. Here, we developed colonoid lines from pediatric patients with endoscopically active UC, inactive UC, and those without endoscopic or histologic evidence of colon inflammation (non-IBD controls) to interrogate functional metabolic differences in the colon epithelia. We demonstrate that colonoids from active UC patients exhibit hypermetabolic features and cellular stress, specifically during differentiation. Hypermetabolism in differentiating active UC colonoids was driven, in part, by increased proton leak, and supported by enhanced glycolytic capacity and dysregulated neutral lipid accumulation. Transcriptomic and pathway analyses indicated a role for PPAR-α in lipid-induced hypermetabolism in aUC colonoids, which was validated by PPAR-α activation in non-IBD colonoids. Accordingly, limiting neutral lipid accumulation in active UC colonoids through pharmacological inhibition of PPAR-α induced a metabolic shift towards glucose utilization, suppressed hypermetabolism and chemokine secretion, and improved markers of cellular stress and epithelial differentiation. Taken together, we reveal a role for lipid-related metabolic dysfunction in the pediatric UC epithelium and support the advancement of colonoids as a preclinical human model for testing epithelial-directed therapies against such metabolic dysfunction.

Homeostasis and function of regulatory T cells in HIV/SIV infection.

Regulatory T cells (Tregs) play a pivotal role in the maintenance of tolerance as well as in the control of immune activation, particularly during chronic infections. In the setting of HIV infection, the majority of studies have reported an increase in Treg frequency but a decrease in absolute number in all immune compartments of HIV-infected individuals. Several nonexclusive mechanisms have been postulated to explain this preferential Treg accumulation, including peripheral survival, increased proliferation, increased peripheral conversion, and tissue redistribution. The role played by Tregs during HIV infection is still poorly understood, as two opposing hypotheses have been proposed. A detrimental role of Tregs during HIV infection was suggested based on the evidence that Tregs suppress virus-specific immune responses. Conversely, Tregs could be beneficial by limiting immune activation, thus controlling the availability of HIV targets as well as preventing immune-based pathologies. Despite the technical difficulties, getting a better understanding of the mechanisms regulating Treg dynamics remains important, as it will help determine whether we can successfully manipulate Treg function or number to the advantage of the infected host. The aim of this review is thus to discuss the recent findings on Treg homeostasis and function in the setting of HIV infection.

Regulatory T cells control HIV replication in activated T cells through a cAMP-dependent mechanism.

We hypothesized that regulatory T cells (Tregs) could play a beneficial role during HIV infection by controlling HIV replication in conventional T cells (Tcons). Purified Tregs and Tcons from healthy donors were activated separately. Tcons were infected with the X4 or R5 HIV strains and cultured with or without autologous Tregs. Coculture of Tcons and Tregs resulted in a dose-dependent inhibition of Tcon infection, which was significant when a 1:1 Treg:Tcon ratio was used. Treg suppression of HIV infection was largely mediated by contact-dependent mechanisms. Blockage of cytotoxic T-lymphocyte-associated antigen-4 did not significantly reduce Treg function. In contrast, Tregs acted through cAMP-dependent mechanisms, because the decrease of cAMP levels in Tregs, the blockade of gap junction formation between Tregs and Tcons, the blockage of CD39 activity, and the blockage of protein kinase A in Tcons all abolished Treg-mediated suppression of HIV replication. Our data suggest a complex role for Tregs during HIV infection. Although Tregs inhibit specific immune responses, their inhibition of HIV replication in Tcons may play a beneficial role, particularly during early HIV infection, when the effector immune cells are not yet activated. Such a protective role of Tregs could have a profound impact on infection outcome.

Bcl-2 allows effector and memory CD8+ T cells to tolerate higher expression of Bim.

As acute infections resolve, most effector CD8(+) T cells die, whereas some persist and become memory T cells. Recent work showed that subsets of effector CD8(+) T cells, identified by reciprocal expression of killer cell lectin-like receptor G1 (KLRG1) and CD127, have different lifespans. Similar to previous reports, we found that effector CD8(+) T cells reported to have a longer lifespan (i.e., KLRG1(low)CD127(high)) have increased levels of Bcl-2 compared with their shorter-lived KLRG1(high)CD127(low) counterparts. Surprisingly, we found that these effector KLRG1(low)CD127(high) CD8(+) T cells also had increased levels of Bim compared with KLRG1(high)CD127(low) cells. Similar effects were observed in memory cells, in which CD8(+) central memory T cells expressed higher levels of Bim and Bcl-2 than did CD8(+) effector memory T cells. Using both pharmacologic and genetic approaches, we found that survival of both subsets of effector and memory CD8(+) T cells required Bcl-2 to combat the proapoptotic activity of Bim. Interestingly, inhibition or absence of Bcl-2 led to significantly decreased expression of Bim in surviving effector and memory T cells. In addition, manipulation of Bcl-2 levels by IL-7 or IL-15 also affected expression of Bim in effector CD8(+) T cells. Finally, we found that Bim levels were significantly increased in effector CD8(+) T cells lacking Bax and Bak. Together, these data indicate that cells having the highest levels of Bim are selected against during contraction of the response and that Bcl-2 determines the level of Bim that effector and memory T cells can tolerate.

The bidirectional immune crosstalk in metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an unabated risk factor for end-stage liver diseases with no available therapies. Dysregulated immune responses are critical culprits of MASLD pathogenesis. Independent contributions from either the innate or adaptive arms of the immune system or their unidirectional interplay are commonly studied in MASLD. However, the bidirectional communication between innate and adaptive immune systems and its impact on MASLD remain insufficiently understood. Given that both innate and adaptive immune cells are indispensable for the development and progression of inflammation in MASLD, elucidating pathogenic contributions stemming from the bidirectional interplay between these two arms holds potential for development of novel therapeutics for MASLD. Here, we review the immune cell types and bidirectional pathways that influence the pathogenesis of MASLD and highlight potential pharmacologic approaches to combat MASLD based on current knowledge of this bidirectional crosstalk.

Obesity amplifies influenza virus-driven disease severity in male and female mice.

Influenza virus-induced respiratory pneumonia remains a major public health concern. Obesity, metabolic diseases, and female sex are viewed as independent risk factors for worsened influenza virus-induced lung disease severity. However, lack of experimental models of severe obesity in female mice limits discovery-based studies. Here, via utility of thermoneutral housing (30 °C) and high-fat diet (HFD) feeding, we induced severe obesity and metabolic disease in female C57BL/6 mice and compared their responses to severely obese male C57BL/6 counterparts during influenza virus infection. We show that lean male and female mice have similar lung edema, inflammation, and immune cell infiltration during influenza virus infection. At standard housing conditions, HFD-fed male, but not female, mice exhibit severe obesity, metabolic disease, and exacerbated influenza disease severity. However, combining thermoneutral housing and HFD feeding in female mice induces severe obesity and metabolic disease, which is sufficient to amplify influenza virus-driven disease severity to a level comparable to severely obese male counterparts. Lastly, increased total body weights of male and female mice at time of infection correlated with worsened influenza virus-driven disease severity metrics. Together, our findings confirm the impact of obesity and metabolic disease as key risk factors to influenza disease severity and present a novel mouse experimental model suitable for future mechanistic interrogation of sex, obesity, and metabolic disease traits in influenza virus-driven disease severity.

Thermoneutral housing shapes hepatic inflammation and damage in mouse models of non-alcoholic fatty liver disease.

Introduction: Inflammation is a common unifying factor in experimental models of non-alcoholic fatty liver disease (NAFLD) progression. Recent evidence suggests that housing temperature-driven alterations in hepatic inflammation correlate with exacerbated hepatic steatosis, development of hepatic fibrosis, and hepatocellular damage in a model of high fat diet-driven NAFLD. However, the congruency of these findings across other, frequently employed, experimental mouse models of NAFLD has not been studied. Methods: Here, we examine the impact of housing temperature on steatosis, hepatocellular damage, hepatic inflammation, and fibrosis in NASH diet, methionine and choline deficient diet, and western diet + carbon tetrachloride experimental models of NAFLD in C57BL/6 mice. Results: We show that differences relevant to NAFLD pathology uncovered by thermoneutral housing include: (i) augmented NASH diet-driven hepatic immune cell accrual, exacerbated serum alanine transaminase levels and increased liver tissue damage as determined by NAFLD activity score; (ii) augmented methionine choline deficient diet-driven hepatic immune cell accrual and increased liver tissue damage as indicated by amplified hepatocellular ballooning, lobular inflammation, fibrosis and overall NAFLD activity score; and (iii) dampened western diet + carbon tetrachloride driven hepatic immune cell accrual and serum alanine aminotransferase levels but similar NAFLD activity score. Discussion: Collectively, our findings demonstrate that thermoneutral housing has broad but divergent effects on hepatic immune cell inflammation and hepatocellular damage across existing experimental NAFLD models in mice. These insights may serve as a foundation for future mechanistic interrogations focused on immune cell function in shaping NAFLD progression.

BAFF and APRIL counterregulate susceptibility to inflammation-induced preterm birth.

Clinical evidence points to a function for B cell-activating factor (BAFF) in pregnancy. However, direct roles for BAFF-axis members in pregnancy have not been examined. Here, via utility of genetically modified mice, we report that BAFF promotes inflammatory responsiveness and increases susceptibility to inflammation-induced preterm birth (PTB). In contrast, we show that the closely related A proliferation-inducing ligand (APRIL) decreases inflammatory responsiveness and susceptibility to PTB. Known BAFF-axis receptors serve a redundant function in signaling BAFF/APRIL presence in pregnancy. Treatment with anti-BAFF/APRIL monoclonal antibodies or BAFF/APRIL recombinant proteins is sufficient to manipulate susceptibility to PTB. Notably, macrophages at the maternal-fetal interface produce BAFF, while BAFF and APRIL presence divergently shape macrophage gene expression and inflammatory function. Overall, our findings demonstrate that BAFF and APRIL play divergent inflammatory roles in pregnancy and provide therapeutic targets for mitigating risk of inflammation-induced PTB.

Thermoneutral Housing Enables Studies of Vertical Transmission of Obesogenic Diet-Driven Metabolic Diseases.

Vertical transmission of obesity is a critical contributor to the unabated obesity pandemic and the associated surge in metabolic diseases. Existing experimental models insufficiently recapitulate "human-like" obesity phenotypes, limiting the discovery of how severe obesity in pregnancy instructs vertical transmission of obesity. Here, via utility of thermoneutral housing and obesogenic diet feeding coupled to syngeneic mating of WT obese female and lean male mice on a C57BL/6 background, we present a tractable, more "human-like" approach to specifically investigate how maternal obesity contributes to offspring health. Using this model, we found that maternal obesity decreased neonatal survival, increased offspring adiposity, and accelerated offspring predisposition to obesity and metabolic disease. We also show that severe maternal obesity was sufficient to skew offspring microbiome and create a proinflammatory gestational environment that correlated with inflammatory changes in the offspring in utero and adulthood. Analysis of a human birth cohort study of mothers with and without obesity and their infants was consistent with mouse study findings of maternal inflammation and offspring weight gain propensity. Together, our results show that dietary induction of obesity in female mice coupled to thermoneutral housing can be used for future mechanistic interrogations of obesity and metabolic disease in pregnancy and vertical transmission of pathogenic traits.

Low-level HIV infection of hepatocytes.

BACKGROUND: There are only limited data on whether HIV infection occurs within the liver; therefore, we explored early and late stages of the HIV life cycle in two hepatocyte cell lines--Huh7.5 and Huh7.5JFH1--as well as in primary human hepatocytes. RESULTS: Integrated HIV DNA was detected in Huh7.5 and Huh7.5JFH1 cells, as well as in primary hepatocytes, and was inhibited by the integrase inhibitor raltegravir in a dose-dependent manner. HIV p24 protein was also detected in cell culture supernatants at days 1, 3, 5, and 7 post-infection and was inhibited by AZT, although levels were modest compared to those in a lymphocyte cell line. Culture supernatants from HIV-infected hepatocytes were capable of infecting a non-hepatic HIV indicator cell line. CONCLUSIONS: These results indicating low-level HIV replication in hepatoctyes in vitro complement evidence suggesting that HIV has deleterious effects on the liver in vivo.

Microbial metabolite butyrate promotes induction of IL-10+IgM+ plasma cells.

The microbially-derived short-chain fatty acid butyrate is a central inhibitor of inflammatory innate and adaptive immune responses. Emerging evidence suggests that butyrate induces differentiation of IL-10-producing (IL-10+) regulatory B cells. However, the underlying mechanisms of butyrate-driven modulation of B cell differentiation are not fully defined. Given the dominant role of regulatory plasma cells (PCs) as the main source of anti-inflammatory cytokines including IL-10 and the observation that butyrate also induces the differentiation of PCs, we here investigated the effect of the microbial metabolite butyrate on the induction of regulatory IL-10+ PCs and underlying mechanisms. Here we show that butyrate induces the differentiation of IL-10+IgM+ PCs. Ex vivo, butyrate, but hardly propionate, another microbially-derived short-chain fatty acid, induced the differentiation of IL-10+IgM+ CD138high PCs from isolated splenic murine B cells. In vivo, administration of butyrate via drinking water or by daily intraperitoneal injection increased the number of IL-10+IgM+ CD138high PCs in the spleens of Ovalbumin (Ova)/complete Freund's adjuvant-immunized mice. The induction of these regulatory PCs was associated with an increase of anti-Ova IgM, but a reduction of anti-Ova class-switched pathogenic IgG2b serum antibodies. Based on the knowledge that butyrate inhibits histone deacetylases (HDACs) thereby increasing histone acetylation, we identified here that HDAC3 inhibition was sufficient to induce PC differentiation and IL-10+ expression. Furthermore, reduced mitochondrial superoxide levels following butyrate treatment and HDAC3 inhibition were necessary for PC differentiation, but not IL-10 expression. In summary, the microbial metabolite butyrate promotes the differentiation of IgM+ PCs and their expression of IL-10. HDAC3 inhibition may be involved as an underlying pathway for both PC differentiation and IL-10 expression, while reduced mitochondrial superoxide levels are crucial only for PC differentiation. The induction of regulatory IL-10+IgM+ PCs and the inhibition of class switching to antigen-specific pathogenic IgG subclasses might represent important pathways of butyrate to limit inflammation.

The tendency to stop collecting information is linked to illusions of causality.

Previous research proposed that cognitive biases contribute to produce and maintain the symptoms exhibited by deluded patients. Specifically, the tendency to jump to conclusions (i.e., to stop collecting evidence soon before making a decision) has been claimed to contribute to delusion formation. Additionally, deluded patients show an abnormal understanding of cause-effect relationships, often leading to causal illusions (i.e., the belief that two events are causally connected, when they are not). Both types of bias appear in psychotic disorders, but also in healthy individuals. In two studies, we test the hypothesis that the two biases (jumping to conclusions and causal illusions) appear in the general population and correlate with each other. The rationale is based on current theories of associative learning that explain causal illusions as the result of a learning bias that tends to wear off as additional information is incorporated. We propose that participants with higher tendency to jump to conclusions will stop collecting information sooner in a causal learning study than those participants with lower tendency to jump to conclusions, which means that the former will not reach the learning asymptote, leading to biased judgments. The studies provide evidence in favour that the two biases are correlated but suggest that the proposed mechanism is not responsible for this association.

A protocol for isolation of primary human immune cells from the liver and mesenteric white adipose tissue biopsies.

Isolation of viable immune cells from human tissues is critical for the characterization of cellular and molecular processes underlying disease pathogenesis. Here, we describe protocols for the isolation of highly viable immune cells from liver wedges and mesenteric white adipose tissue resections from obese persons. Notably, characterization of the isolated single-immune cell suspensions, via utility of basic immunological interrogations and genetic approaches, promises to generate an improved understanding of altered immunological pathways in obese individuals with or without metabolic diseases. For complete details on the use and execution of this protocol, please refer to Moreno-Fernandez et al. (2021).

Implications of Inflammatory States on Dysfunctional Immune Responses in Aging and Obesity.

Aging and obesity are two conditions characterized by chronic, low-grade inflammation. While both conditions are also associated with dysfunctional immune responses, the shared and distinct underlying mechanisms are just starting to be uncovered. In fact, recent findings have suggested that the effects of obesity on the immune system can be thought of as a state of accelerated aging. Here we propose that chronic, low-grade inflammation seen in obesity and aging is complex, affects multiple cell types, and results in an altered basal immune state. In aging, part of this altered state is the emergence of regulatory immune populations that lead to further immune dysfunction in an attempt to reduce chronic inflammation. While in obesity, part of the altered state is the effect of expanding adipose tissue on immune cell function. Thus, in this review, we compare, and contrast altered immune states in aging and obesity and discuss their potential contribution to a shared clinical problem- decreased vaccine responsiveness.