Mast cells control lung type 2 inflammation via prostaglandin E2-driven soluble ST2.

Severe asthma and sinus disease are consequences of type 2 inflammation (T2I), mediated by interleukin (IL)-33 signaling through its membrane-bound receptor, ST2. Soluble (s)ST2 reduces available IL-33 and limits T2I, but little is known about its regulation. We demonstrate that prostaglandin E2 (PGE2) drives production of sST2 to limit features of lung T2I. PGE2-deficient mice display diminished sST2. In humans with severe respiratory T2I, urinary PGE2 metabolites correlate with serum sST2. In mice, PGE2 enhanced sST2 secretion by mast cells (MCs). Mice lacking MCs, ST2 expression by MCs, or E prostanoid (EP)2 receptors by MCs showed reduced sST2 lung concentrations and strong T2I. Recombinant sST2 reduced T2I in mice lacking PGE2 or ST2 expression by MCs back to control levels. PGE2 deficiency also reversed the hyperinflammatory phenotype in mice lacking ST2 expression by MCs. PGE2 thus suppresses T2I through MC-derived sST2, explaining the severe T2I observed in low PGE2 states.

Limb, sex, but not acute dietary capsaicin, modulate the near-infrared spectroscopy-vascular occlusion test estimate of muscle metabolism.

The downward slope during the near-infrared spectroscopy (NIRS)-vascular occlusion test (NIRS-VOT) is purported as a simplified estimate of metabolism. Whether or not the NIRS-VOT exhibits sex- or limb-specificity or may be acutely altered remains to be elucidated. Thus, we investigated if there is limb- or sex specificity in tissue desaturation rates (DeO2) during a NIRS-VOT, and if acute dietary capsaicin may alter this estimate of muscle metabolism. Young healthy men (n = 25, 21 ± 4 years) and women (n = 20, 20 ± 1 years) ingested either placebo or capsaicin, in a counterbalanced, single-blind, crossover design after which a simplified NIRS-VOT was conducted to determine the DeO2 (%/s), as an estimate of oxidative muscle metabolism, in both the forearm (flexors) and thigh (vastus lateralis). There was a significant limb effect with the quadriceps having a greater DeO2 than the forearm (-2.31 ± 1.34 vs. -1.78 ± 1.22%/s, p = 0.007, ηp 2 = 0.19). There was a significant effect of sex on DeO2 (p = 0.005, ηp 2 = 0.203) with men exhibiting a lesser DeO2 than women (-1.73 ± 1.03 vs. -2.36 ± 1.32%/s, respectively). This manifested in significant interactions of limb*capsaicin (p = 0.001, ηp 2 = 0.26) as well as limb*capsaicin*sex on DeO2 (p = 0.013, ηp 2 = 0.16) being observed. Capsaicin does not clearly alter O2-dependent muscle metabolism, but there was apparent limb and sex specificity, interacting with capsaicin in this NIRS-derived assessment.

Pla2g5 contributes to viral-like-induced lung inflammation through macrophage proliferation and LA/Ffar1 lung cell recruitment.

Macrophages expressing group V phospholipase A2 (Pla2g5) release the free fatty acid (FFA) linoleic acid (LA), potentiating lung type 2 inflammation. Although Pla2g5 and LA increase in viral infections, their role remains obscure. We generated Pla2g5flox/flox mice, deleted Pla2g5 by using the Cx3cr1cre transgene, and activated bone marrow-derived macrophages (BM-Macs) with poly:IC, a synthetic double-stranded RNA that triggers a viral-like immune response, known Pla2g5-dependent stimuli (IL-4, LPS + IFNγ, IL-33 + IL-4 + GM-CSF) and poly:IC + LA followed by lipidomic and transcriptomic analysis. Poly:IC-activated Pla2g5flox/flox;Cx3cr1cre/+ BM-Macs had downregulation of major bioactive lipids and critical enzymes producing those bioactive lipids. In addition, AKT phosphorylation was lower in poly:IC-stimulated Pla2g5flox/flox;Cx3cr1cre/+ BM-Macs, which was not restored by adding LA to poly:IC-stimulated BM-Macs. Consistently, Pla2g5flox/flox;Cx3cr1cre/+ mice had diminished poly:IC-induced lung inflammation, including inflammatory macrophage proliferation, while challenging Pla2g5flox/flox;Cx3cr1cre/+ mice with poly:IC + LA partially restored lung inflammation and inflammatory macrophage proliferation. Finally, mice lacking FFA receptor-1 (Ffar1)-null mice had reduced poly:IC-induced lung cell recruitment and tissue macrophage proliferation, not corrected by LA. Thus, Pla2g5 contributes to poly:IC-induced lung inflammation by regulating inflammatory macrophage proliferation and LA/Ffar1-mediated lung cell recruitment and tissue macrophage proliferation.

Sex differences in estimates of cardiac autonomic function using heart rate variability: effects of dietary capsaicin.

PURPOSE: Heart rate variability (HRV) estimates the autonomic nervous system (ANS) influence on the heart and appears sex-specific. Sensory afferents exhibit sex-specificity; although, it is unknown if Capsaicin, an agonist for transient receptor potential vanilloid channel-1 (TRPV1), alters cardiac ANS activity in a sex-dependent manner, which could be important given the predictive nature of HRV on risk of developing hypertension. Thus, we explored if there was sex-specificity in the effect of capsaicin on estimated cardiac ANS activity. METHODS: HRV was measured in 38 young males (M: n = 25) and females (F: n = 13), in a blinded-crossover design, after acute ingestion of placebo or capsaicin. Resting HR, RR-interval, root-mean-square of successive differences (RMSSD), natural log-transformed RMSSD (LnRMSSD), standard deviation of n-n intervals (SDNN), number of pairs of successive n-n intervals differing by > 50 ms (NN50), and percent NN50 (PNN50) were obtained using standard techniques. RESULTS: Significant sex differences were observed in mean HR (M: 59 ± 9.3 vs. F: 65 ± 12 beats/min, p = 0.036, η2 = 0.098), minimum HR (M: 47 ± 8.3 vs. F: 56 ± 12 beats/min, p = 0.014, η2 = 0.124), and NN50 (M: 177 ± 143 vs. F: 29 ± 17, p < 0.001, η2 = 0.249). There was a significant interaction of sex*treatment (p = 0.02, η2 = 0.027) for RMSSD, where males increased (78 ± 55 vs. 91 ± 64 ms), and females decreased (105 ± 83 vs. 76 ± 43 ms), placebo vs. capsaicin. CONCLUSION: This controlled study recapitulates sex differences in HR and HRV, but revealed a sexual dimorphism in the parasympathetic response to capsaicin, perhaps due to differing TRPV1-afferent sensitivity, highlighting a potential mechanism for differential regulation of hemodynamics, and CVD risk, and should be considered in future studies.

Does sex influence near-infrared spectroscopy-derived indicators of microvascular reactivity and the response to acute dietary capsaicin.

Endothelial dysfunction is associated with cardiovascular disease development, nitric oxide (NO) deficiencies, and may be limb or sex-specific. Prior in vitro work indicated that the transient receptor potential vanilloid channel-1 (TRPV1) is expressed in human arteries and the TRPV1 agonist capsaicin alters vasodilation in an endothelium-dependent manner; however, it is unknown if this translates in vivo or is limb or sex-dependent. Therefore, we sought to determine if there was limb or sex-specificity in the effect of capsaicin on microvascular function using near-infrared spectroscopy (NIRS)-derived tissue oxygen saturation (StO2) reperfusion slope. In a blinded placebo-controlled crossover design, 45 young males (M: n = 25) and females (F: n = 20), the reperfusion slopes of the forearm and quadriceps were assessed, and a urine sample obtained to assay for nitrate/nitrite (NOx) concentrations and antioxidant capacity after acutely ingesting placebo or capsaicin. Under placebo, females had greater reperfusion rates in both the forearm (M: 0.44 ± 0.24 vs. F: 0.98 ± 0.46 %/sec; p = 0.002, d = -1.50) and quadricep (M: 0.86 ± 0.31 vs. F: 1.17 ± 0.43 %/sec; p = 0.010, d = -0.85). Capsaicin decreased microvascular responsiveness in the forearm of females (placebo: 0.98 ± 0.45 vs. capsaicin: 0.84 ± 0.45 %/sec) as compared to males (placebo: 0.45 ± 0.24 vs. capsaicin: 0.38 ± 0.16 %/sec, interaction p < 0.001, η2 = 0.475). There was a sex*treatment interaction for NOx concentrations, where males increased (placebo: 21.13 ± 12.83 vs. capsaicin: 23.82 ± 13.34 µM), while females decreased (placebo: 22.78 ± 14.40 vs. capsaicin: 14.43 ± 10.01 µM; p = 0.037, η2 = 0.042). Using NIRS to assess microvascular function, there is apparent limb and sex-specificity, and, for the first-time, document that acute oral capsaicin alters reperfusion slope in a sexually divergent manner.

The effect of succinic acid on the metabolic profile in high-fat diet-induced obesity and insulin resistance.

Obesity, insulin resistance, and poor metabolic profile are hallmarks of a high-fat diet (HFD), highlighting the need to understand underlying mechanisms. Therefore, we sought to determine the effect of succinic acid (SA) on metabolism in high-fat diet (HFD)-induced obesity. Animals were randomly assigned to either low-fat diet (LFD) or a high-fat diet (HFD). Mice consumed their respective diets for 4.5 months and then assigned to the following groups: (LFD)+vehicle, LFD + SA (0.75 mg/ml), HFD + vehicle, or HFD + SA. Body weight (BW), food, and water intake, were tracked weekly. After 6 weeks, insulin, glucose, and pyruvate tolerance tests were completed, and spontaneous physical activity was assessed. Epididymal white adipose tissue (EWAT) mass and in vitro measurements of oxidative skeletal muscle (soleus) respiration were obtained. Expectedly, the HFD increased BW and EWAT mass, and reduced glucose and insulin tolerance. SA significantly reduced EWAT mass, more so in HFD (p < .05), but had no effect on any in vivo measurements (BW, insulin, glucose, or pyruvate tolerance, nor physical activity, all p > .05). A significant (p < .05) interaction was observed between mitochondrial respiration and treatment, where SA increased respiration, likely owed to greater mitochondrial content, as assessed by complex IV activity in both LFD and HFD. In HFD-induced obesity, coupled with insulin desensitization, we found no favorable effect of succinic acid on glucose regulation, though adiposity was attenuated. In oxidative skeletal muscle, there was a tendency for increased respiratory capacity, likely owed to greater mitochondrial content, suggestive of a succinic acid-induced mitochondrial biogenesis.