Obesity can lead to type 2 diabetes and is an epidemic. A major contributor to its adverse effects is inflammation of the visceral adipose tissue (VAT). Lifelong caloric restriction (CR), in contrast, results in extended lifespan, enhanced glucose tolerance/insulin sensitivity, and other favorable phenotypes. The effects of CR following obesity are incompletely established, but studies show multiple benefits. Many leukocyte types, macrophages predominantly, reside in VAT in homeostatic and pathological states. CR following obesity transiently increases VAT macrophage content prior to resolution of inflammation and obesity, suggesting that macrophage content and phenotype play critical roles. Here, we examined the heterogeneity of VAT leukocytes and the effects of obesity and CR. In general, our single-cell RNA-sequencing data demonstrate that macrophages are the most abundant and diverse subpopulation of leukocytes in VAT. Obesity induced significant transcriptional changes in all 15 leukocyte subpopulations, with many genes showing coordinated changes in expression across the leukocyte subpopulations. Additionally, obese VAT displayed expansion of one major macrophage subpopulation, which, in silico, was enriched in lipid binding and metabolic processes. This subpopulation returned from dominance in obesity to lean proportions after only 2 weeks of CR, although the pattern of gene expression overall remained similar. Surprisingly, CR VAT is dominated by a different macrophage subpopulation, which is absent in lean conditions. This subpopulation is enriched in genes related to phagocytosis and we postulate that its function includes clearance of dead cells, as well as excess lipids,

Atherosclerosis is a disease of chronic inflammation. We investigated the roles of the cytokines IL-4 and IL-13, the classical activators of STAT6, in the resolution of atherosclerosis inflammation. Using Il4-/-Il13-/- mice, resolution was impaired, and in control mice, in both progressing and resolving plaques, levels of IL-4 were stably low, and IL-13 was undetectable. This suggested that IL-4 is required for atherosclerosis resolution, but collaborates with other factors. We had observed increased Wnt signaling in macrophages in resolving plaques, and human genetic data from others showed that a loss-of-function Wnt mutation was associated with premature atherosclerosis. We now find an inverse association between activation of Wnt signaling and disease severity in mice and humans. Wnt enhanced the expression of inflammation resolving factors after treatment with plaque-relevant low concentrations of IL-4. Mechanistically, activation of the Wnt pathway following lipid lowering potentiates IL-4 responsiveness in macrophages via a PGE2/STAT3 axis.

Peroxynitrite, a transient reactive oxygen species (ROS), is believed to play a deleterious role in physiological processes. Herein, we report a two-photon ratiometric fluorescent probe that selectively reacts with peroxynitrite yielding a >200-fold change upon reaction. The probe effectively visualized fluctuations in peroxynitrite generation by arginase 1 in vivo and in vitro. This provides evidence that arginase 1 is a critical regulator of peroxynitrite.

Since alterations in the intestinal microbiota may induce systemic inflammation and polarization of macrophages to the M1 state, the microbiome role in atherosclerosis, an M1-driven disease, requires evaluation. We aimed to determine if antibiotic (Abx) induced alterations to the intestinal microbiota interferes with atherosclerotic plaque inflammation resolution after lipid-lowering in mice. Hyperlipidemic Apoe−/− mice were fed a western diet to develop aortic atherosclerosis with aortas then transplanted into normolipidemic wild-type (WT) mice to model clinically aggressive lipid management and promote atherosclerosis inflammation resolution. Gut microbial composition pre and post-transplant was altered via an enteral antibiotic or not. Post aortic transplant, after Abx treatment, while plaque size did not differ, compared to Apoe−/− mice, Abx– WT recipient mice had a 32% reduction in CD68-expressing cells (p = 0.02) vs. a non-significant 12% reduction in Abx+ WT mice. A trend toward an M1 plaque CD68-expresing cell phenotype was noted in Abx+ mice. By 16S rRNA sequence analysis, the Abx+ mice had reduced alpha diversity and increased Firmicutes/Bacteroidetes relative abundance ratio with a correlation between gut Firmicutes abundance and plaque CD68-expressing cell content (p < 0.05). These results indicate that in a murine atherosclerotic plaque inflammation resolution model, antibiotic-induced microbiome perturbation may blunt the effectiveness of lipid-lowering to reduce the content of plaque inflammatory CD68-expressing cells.

Background: Interleukin-37 (IL-37) is member 7 of the IL-1 family and inhibits pro-inflammatory factor activities. Cervical carcinoma is a malignant tumor associated with inflammation. The roles of IL-37 in the occurrence and progression of cervical cancer have not been elucidated. This study investigated the roles of IL-37 in the proliferation, survival, invasion, and migration of cervical cancer cells. Methods: Cell viability in IL-37-treated HeLa cells was measured using MTT assay. Cell cycle and apoptosis were analyzed with flow cytometry. The invasion, and migration, of cells was tested using the Transwell approach. STAT3, MMP-2, and MMP-9 protein expression was measured with Western blot. Results: In HeLa cells, L-37 treatment significantly reduced viability, increased the percentage of G0/G1 cells, and induced cell apoptosis in a dose-and time-dependent manner (p < 0.05). For cervical carcinoma cells, IL-37 treatment significantly inhibited their invasion and migration, and lowered STAT3, MMP-2, and MMP-9 protein expression (p < 0.05). Conclusion: IL-37 functions as a tumor suppressor in cervical cancer cells by inhibiting cell proliferation, cell cycling, and invasion/migration possibly through hindering the STAT3-MMP-2/MMP-9 signaling. http://mo.qingres.com The Role of IL-37 in Cervical Tumor Cells Xuemei Yang et al

While weight loss is highly recommended for those with obesity, >60% will regain their lost weight. This weight cycling is associated with elevated risk of cardiovascular disease, relative to never having lost weight. How weight loss/regain directly influence atherosclerotic inflammation is unknown. Thus, we studied short-term caloric restriction (stCR) in obese hypercholesterolemic mice, without confounding effects from changes in diet composition. Weight loss was found to promote atherosclerosis resolution independent of plasma cholesterol. From single-cell RNA-sequencing and subsequent mechanistic studies, this can be partly attributed to a unique subset of macrophages accumulating with stCR in epididymal adipose tissue (eWAT) and atherosclerotic plaques. These macrophages, distinguished by high expression of Fcgr4, help to clear necrotic cores in atherosclerotic plaques. Conversely, weight regain (WR) following stCR accelerated atherosclerosis progression with disappearance of Fcgr4+ macrophages from eWAT and plaques. Furthermore, WR caused reprogramming of immune progenitors, sustaining hyper-inflammatory responsiveness. In summary, we have developed a model to investigate the inflammatory effects of weight cycling on atherosclerosis and the interplay between adipose tissue, bone marrow, and plaques. The findings suggest potential approaches to promote atherosclerotic plaque resolution in obesity and weight cycling through induction of Fcgr4+ macrophages and inhibition of immune progenitor reprogramming.

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Background: Adults with congenital heart disease (ACHD) have increased prevalence of mood and anxiety disorders. There are limited data regarding the influence of the COVID-19 pandemic on the mental health and health behaviors of these patients. Objective: The purpose is to evaluate the perceptions, emotions, and health behaviors of ACHD patients during the COVID-19 pandemic. Methods: In this cross-sectional study of ACHD patients, we administered surveys evaluating self-reported emotions, perceptions and health behaviors. Logistic regressions were performed to determine the adjusted odds of displaying each perception, emotion and health behavior based on predictor variables. Results: Ninety-seven patients (mean age 38.3 years, 46.4% female, 85.6% moderate or complex lesion) completed the survey. The majority of patients reported feeling moderately or very sad (63.1%), and 48.4% of patients identified themselves as feeling moderately or very anxious. The majority of patients perceived their risk of COVID-19 as moderate or high. Females were more likely to report feeling sad and anxious (95% CI 1.06-10.96, p-value 0.039, and 95% CI 1.44-15.30, p-value = 0.012, respectively), and were associated with higher odds of having a perceived increased risk of COVID-19 (95% CI 1.33-10.59, p-value 0.012). There was no association between ACHD anatomic or physiologic classification and perceptions, emotions and health behaviors. Conclusions: Females were more likely to report feeling sad, anxious and an increased risk of COVID-19 in comparison to males. These findings indicate the need for mental health support and promotion of health behaviors during the pandemic amongst all ACHD patients, regardless of underlying condition.