Silencing Myeloid Netrin-1 Induces Inflammation Resolution and Plaque Regression.

[Figure: see text].

Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice.

Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα plays a central role in the transcription of inflammatory and metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the consequences of LXRα pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXRα phosphorylation, bone marrow from LXRα WT and S196A mice was transplanted into Ldlr-/- mice, which were fed a western diet prior to evaluation of atherosclerosis and obesity. Plaques from S196A mice showed reduced inflammatory monocyte recruitment, lipid accumulation, and macrophage proliferation. Expression profiling of CD68+ and T cells from S196A mouse plaques revealed downregulation of pro-inflammatory genes and in the case of CD68+ upregulation of mitochondrial genes characteristic of anti-inflammatory macrophages. Furthermore, S196A mice had lower body weight and less visceral adipose tissue; this was associated with transcriptional reprograming of the adipose tissue macrophages and T cells, and resolution of inflammation resulting in less fat accumulation within adipocytes. Thus, reducing LXRα pS196 in hematopoietic cells attenuates atherosclerosis and obesity by reprogramming the transcriptional activity of LXRα in macrophages and T cells to promote an anti-inflammatory phenotype.

Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis.

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.

Sex differences in the prevalence of vascular disease and risk factors in young hospitalized patients with psoriasis.

BACKGROUND: Psoriasis is an inflammatory skin disease associated with atherosclerotic cardiovascular disease (ASCVD) risk factors and vascular disease. The relative impact of psoriasis on vascular disease is the strongest in young patients with psoriasis, yet data are lacking on how sex differences influence cardiovascular risk factors and vascular disease in these patients. OBJECTIVE: This observational study aimed to identify the burden of cardiovascular risk factors and vascular disease in patients with psoriasis and to explore whether this burden is different between men and women age < 35 years. METHODS: Young (age ≥ 20 and < 35 years) hospitalized patients with psoriasis from the United States National Inpatient Sample were compared with those matched patients without psoriasis. Vascular disease was defined as ASCVD and/or venous thromboembolic disease. Multivariable logistic regression was used to determine the associations between psoriasis, sex, ASCVD risk factors, and vascular disease. RESULTS: Overall, patients with psoriasis (n = 18,353) were more often obese (16% vs. 6%); smokers (31% vs. 17%); and diagnosed with diabetes mellitus (10% vs. 6%), hypertension (16% vs. 8%), hyperlipidemia (6% vs. 2%), ASCVD (2.2% vs. 1.6%), and deep vein thrombosis (6% vs. 4%; all p < .001) compared with patients without psoriasis (n = 55,059; matched by age, sex, and race). When stratified by sex, women with psoriasis were more likely to have multiple cardiovascular risk factors and ASCVD (odds ratio: 2.6; 95% confidence interval [2.1-3.1]) compared with men with psoriasis (odds ratio: 1.2; 95% confidence interval [0.9-1.4]; interaction p < .01). The association between psoriasis and ASCVD in women remained unchanged after multivariable adjustment for traditional cardiovascular risk factors. CONCLUSION: Psoriasis was associated with cardiovascular disease and risk factors in young hospitalized patients, with stronger associations among women than among men.