A defining feature of resident gut macrophages is their high replenishment rate from blood monocytes attributed to tonic commensal stimulation of this site. In contrast, almost all other tissues ...contain locally maintained macrophage populations, which coexist with monocyte-replenished cells at homeostasis. In this study, we identified three transcriptionally distinct mouse gut macrophage subsets that segregate based on expression of Tim-4 and CD4. Challenging current understanding, Tim-4
CD4
gut macrophages were found to be locally maintained, while Tim-4
CD4
macrophages had a slow turnover from blood monocytes; indeed, Tim-4
CD4
macrophages were the only subset with the high monocyte-replenishment rate currently attributed to gut macrophages. Moreover, all macrophage subpopulations required live microbiota to sustain their numbers, not only those derived from blood monocytes. These findings oppose the prevailing paradigm that all macrophages in the adult mouse gut rapidly turn over from monocytes in a microbiome-dependent manner; instead, these findings supplant it with a model of ontogenetic diversity where locally maintained subsets coexist with rapidly replaced monocyte-derived populations.
Immune regulation by cytokines is crucial in maintaining immune homeostasis, promoting responses to infection, resolving inflammation, and promoting immunological memory. Additionally, cytokine ...responses drive pathology in immune-mediated disease. A crucial cytokine in the regulation of all aspects of an immune response is transforming growth factor beta (TGFβ). Although best known as a crucial regulator of T cell responses, TGFβ plays a vital role in regulating responses mediated by virtually every innate and adaptive immune cell, including dendritic cells, B cells, NK cells, innate lymphoid cells, and granulocytes. Here, we review our current knowledge of how TGFβ regulates the immune system, highlighting the multifunctional nature of TGFβ and how its function can change depending on location and context of action.
Background: In older adults, every 0.1-m/s slower gait speed is associated with a 12% higher mortality. However, little research has identified risk factors for gait-speed decline.Objective: We ...assessed the association between several measures of body composition and age-related decline in gait speed.Design: Data were from 2306 older adults who were participating in the Health, Aging, and Body Composition cohort and were followed for 4 y (50% women; 38% black). Usual walking speed (m/s) over 20 m was measured in years 2 through 6, and the baseline and changes in several measures of body composition were included in mixed-effects models.Results: Gait speed declined by 0.06 ± 0.00 m/s over the 4-y period. Baseline thigh intermuscular fat predicted the annual gait-speed decline (±SE) in both men and women (−0.01 ± 0.00 and −0.02 ± 0.00 m/s per 0.57 cm2, respectively; P < 0.01). In men, but not in women, this relation was independent of total body adiposity. In longitudinal analyses, changes in thigh intermuscular fat and total thigh muscle were the only body-composition measures that predicted gait-speed decline in men and women combined. When modeled together, every 5.75-cm2 increase in thigh intermuscular fat was associated with a 0.01 ± 0.00-m/s decrease in gait speed, whereas every 16.92-cm2 decrease in thigh muscle was associated with a 0.01 ± 0.00-m/s decrease in gait speed.Conclusions: High and increasing thigh intermuscular fat are important predictors of gait-speed decline, implying that fat infiltration into muscle contributes to a loss of mobility with age. Conversely, a decreasing thigh muscle area is also predictive of a decline in gait speed.
Monocytes are crucial immune cells involved in regulation of inflammation either directly or via differentiation into macrophages in tissues. However, many aspects of how their function is controlled ...in health and disease are not understood. Here we show that human blood monocytes activate high levels of the cytokine TGFβ, a pathway that is not evident in mouse monocytes. Human CD14
, but not CD16
, monocytes activate TGFβ via expression of the integrin αvβ8 and matrix metalloproteinase 14, which dampens their production of TNFα in response to LPS. Additionally, when monocytes differentiate into macrophages, integrin expression and TGFβ-activating ability are maintained in anti-inflammatory macrophages but down-regulated in pro-inflammatory macrophages. In the healthy human intestine, integrin αvβ8 is highly expressed on mature tissue macrophages, with these cells and their integrin expression being significantly reduced in active inflammatory bowel disease. Thus, our data suggest that integrin αvβ8-mediated TGFβ activation plays a key role in regulation of monocyte inflammatory responses and intestinal macrophage homeostasis.
Schizotypy is a multidimensional personality construct that is understood as a vulnerability for schizophrenia, often manifesting as more subtle and attenuated symptoms, referred to as schizotypic ...psychopathology. It has many well-established environmental risk factors, including experiencing childhood maltreatment (CM), but the intermediary mechanisms that relate CM to schizotypic psychopathology are unclear. Prior studies have demonstrated that trait dissociation may indirectly affect the relationship between CM and schizotypic psychopathology. However, less is known about the importance of peritraumatic dissociative experiences during CM and how it relates to schizotypic symptom manifestations in young adulthood. Therefore, the present study explored the independent contributions of peritraumatic and trait dissociation in the relationship between CM and schizotypy. Participants (N = 346) were undergraduate students who completed online self-report measures on CM, trait dissociation, peritraumatic dissociation experienced during CM, and schizotypic symptoms. The indirect effect of peritraumatic dissociation and trait dissociation on the relationship between CM and schizotypy was examined using mediational analyses. Correlational analyses revealed significant associations between self-reported CM, schizotypy, trait dissociation, and peritraumatic dissociation. In addition, mediational analyses indicated a significant indirect effect of peritraumatic dissociation (β = .06, 95% confidence interval (CI) 0.01, 0.12), but not trait dissociation (β = .05, 95% CI −0.02, 0.12), on CM and schizotypy. These results highlight peritraumatic dissociation as an important mechanism driving the expression of schizotypic symptoms among individuals with a history of CM. Understanding how trauma sequelae lead to schizotypic psychopathology may be crucial in assessing and treating individuals with maltreatment histories or those on the psychosis spectrum.
Succinobucol is a phenolic antioxidant with anti-inflammatory and antiplatelet effects. Given the importance of oxidant stress in modulating platelet-platelet and platelet-vessel wall interactions, ...the aim of this study was to establish if antioxidant activity was responsible for the antiplatelet activity of succinobucol. Platelet aggregation in response to collagen and adenosine diphosphate (ADP) was studied in rabbit whole blood and platelet-rich plasma using impedance aggregometry. The effect of oxidant stress on aggregation, platelet lipid peroxides, and vascular tone was studied by incubating platelets, washed platelets or preconstricted rabbit iliac artery rings respectively with a combination of xanthine and xanthine oxidase (X/XO). To study the effect of succinobucol in vivo, anaesthetized rats were injected with up to 150 mg/kg succinobucol and aggregation measured in blood removed 15 mins later. Succinobucol (10
−5
-10
−4
M) significantly attenuated platelet aggregation to collagen and ADP in whole blood and platelet-rich plasma. X/XO significantly increased aggregation to collagen and platelet lipid peroxides and this was reversed by succinobucol. Addition of X/XO to denuded rabbit iliac arteries caused a dose-dependent relaxation which was significantly inhibited by succinobucol. In vivo administration up to 150 mg/kg had no effect on heart rate or mean arterial blood pressure but significantly inhibited platelet aggregation to collagen ex vivo. In conclusion, succinobucol displays anti-platelet activity in rabbit and rat blood and reverses the increase in platelet aggregation in response to oxidant stress.
Some preliminary work during the COVID-19 pandemic indicates that adult alcohol use increased, particularly for parents. This cross-sectional study examined the quantity and frequency of adults' ...alcohol use during the early stages of the pandemic. Additionally, the influences of gender, parenthood, COVID-19-related stressors and intimate partner violence (IPV) on alcohol consumption were examined. The sample consisted of 298 adults (98 parents) from across the United States who completed self-report surveys through Qualtrics at the beginning of the pandemic in May 2020. In the present study, all men reported higher levels of drinking compared to all women. Although stress levels did not impact alcohol consumption, findings indicate that increased IPV experiences were associated with higher levels of heavy drinking during the pandemic. Results also suggested that having children in the home particularly impacted drinking levels during the pandemic, above and beyond the influence of gender, IPV, and stress levels. These findings suggest that parenthood may have had a cascading influence on drinking experiences during the COVID-19 pandemic. Implications and recommendations for further research are discussed.
Adherent invasive Escherichia coli (AIEC) have been implicated as a causative agent of Crohn's disease (CD) due to their isolation from the intestines of CD sufferers and their ability to persist in ...macrophages inducing granulomas. The rapid intracellular multiplication of AIEC sets it apart from other enteric pathogens such as Salmonella Typhimurium which after limited replication induce programmed cell death (PCD). Understanding the response of infected cells to the increased AIEC bacterial load and associated metabolic stress may offer insights into AIEC pathogenesis and its association with CD. Here we show that AIEC persistence within macrophages and dendritic cells is facilitated by increased proteasomal degradation of caspase-3. In addition S-nitrosylation of pro- and active forms of caspase-3, which can inhibit the enzymes activity, is increased in AIEC infected macrophages. This S-nitrosylated caspase-3 was seen to accumulate upon inhibition of the proteasome indicating an additional role for S-nitrosylation in inducing caspase-3 degradation in a manner independent of ubiquitination. In addition to the autophagic genetic defects that are linked to CD, this delay in apoptosis mediated in AIEC infected cells through increased degradation of caspase-3, may be an essential factor in its prolonged persistence in CD patients.
Objectives
To examine whether deficient B12 status or low serum B12 levels are associated with worse sensory and motor peripheral nerve function in older adults.
Design
Cross‐sectional.
Setting
...Health, Aging and Body Composition Study.
Participants
Two thousand two hundred and eighty‐seven adults aged 72 to 83 (mean 76.5 ± 2.9; 51.4% female; 38.3% black).
Measurements
Low serum B12 was defined as serum B12 less than 260 pmol/L, and deficient B12 status was defined as B12 less than 260 pmol/L, methylmalonic acid (MMA) greater than 271 nmol/L, and MMA greater than 2‐methylcitrate. Peripheral nerve function was assessed according to peroneal nerve conduction amplitude and velocity (NCV) (motor), 1.4 g/10 g monofilament detection, average vibration threshold detection, and peripheral neuropathy symptoms (numbness, aching or burning pain, or both) (sensory).
Results
B12‐deficient status was found in 7.0% of participants, and an additional 10.1% had low serum B12 levels. B12 deficient status was associated with greater insensitivity to light (1.4 g) touch (odds ratio = 1.50, 95% confidence interval = 1.06–2.13) and worse NCV (42.3 vs 43.5 m/s) (β = −1.16, P = .01) after multivariable adjustment for demographics, lifestyle factors, and health conditions. Associations were consistent for the alternative definition using low serum B12 only. No significant associations were found for deficient B12 status or the alternative low serum B12 definition and vibration detection, nerve conduction amplitude, or peripheral neuropathy symptoms.
Conclusion
Poor B12 (deficient B12 status and low serum B12) is associated with worse sensory and motor peripheral nerve function. Nerve function impairments may lead to physical function declines and disability in older adults, suggesting that prevention and treatment of low B12 levels may be important to evaluate.
PDF
