高脂饮食诱导肥胖小鼠表达卵泡抑素样蛋白1与脂肪组织炎症和棕色脂肪的功能

目的 探讨卵泡抑素样蛋白1（FSTL1）在高脂饮食诱导的肥胖小鼠脂肪炎症中的作用,以及对棕色脂肪功能的影响。 方法 6周龄C57BL/6 J小鼠分为两组,每组8只,给予12周正常饮食（RD）和高脂饮食（HFD）饲养,每周称量小鼠体重,记录小鼠摄食量;12周后,进行糖耐量和胰岛素耐量的检测并取材,称量小鼠的皮下白色脂肪、肾周白色脂肪、附睾白色脂肪和棕色脂肪的重量;HE染色观察小鼠白色脂肪中的冠状结构（CLS）及小鼠棕色脂肪组织变化,RT-PCR分析小鼠附睾白色脂肪炎症因子、肿瘤坏死因子α（TNF-α)、白细胞介素6（IL-6）和白细胞介素10（IL-10）的表达,以及FSTL1的表达;Western blotting检测棕色脂肪解耦联蛋白1（UCP1）与FSTL1蛋白的表达。 结果 与RD小鼠相比,HFD组小鼠的体重增加,摄食量减少,不同部位脂肪重量显著增加,葡萄糖耐受能力显著降低,胰岛素敏感性显著下降,附睾白色脂肪观察到炎症反应CLS且附睾白色脂肪中炎症因子TNF-α、IL-6及IL-10表达显著增高, FSTL1表达亦显著增加。Western blotting结果显示,HFD小鼠的棕色脂肪组织中UCP1与FSTL1表达水平均显著性高于RD组。 结论 在高脂饮食诱导的肥胖小鼠中,FSTL1的表达可能与脂肪炎症因子的分泌增加及棕色脂肪的功能有一定相关性。     

Interleukin-17/interleukin-17 receptor axis elicits intestinal neutrophil migration,restrains gut dysbiosis and lipopolysaccharide translocation in high-fat diet-induced metabolic syndrome model

Sound evidence supports a role for interleukin-17 (IL-17) -producing γδ T cells and IL-17-producing helper T (Th17) cells in intestinal homeostasis, especially in intestinal barrier integrity. In the present study, we aimed to evaluate the role of IL-17 cytokine in the regulation of intestinal immunity and obesity-induced metabolic syndrome (MetS) in an experimental murine model. C57BL/6 wild-type (WT) mice and mice lacking the IL-17 cytokine receptor (IL-17RA^−/−) were fed either a control diet (CD) or a high-fat diet (HFD) for 9 weeks. Our data demonstrate that IL-17RA^−/− mice are protected against obesity, but develop hyperglycemia, hyperinsulinemia and insulin resistance. In parallel, HFD-fed IL-17RA^−/− mice display intense inflammation in the ileum compared with WT mice on the HFD. IL-17RA^−/− mice fed the HFD exhibit impaired neutrophil migration to the intestinal mucosa and reduced gene expression of the CXCL-1 chemokine and CXCR-2 receptor in the ileum. Interestingly, the populations of neutrophils (CD11b⁺ Ly6G⁺) and anti-inflammatory macrophages (CD11b⁺ CX3CR1⁺) are increased in the mesenteric lymph nodes of these mice. IL-17RA^−/− mice on the HFD also display increased commensal bacterial translocation into the bloodstream and elevated lipopolysaccharide (LPS) levels in the visceral adipose tissue (VAT). Metagenomic analysis of bacterial 16S gene revealed increased Proteobacteria and Bacteroidetes phyla, the main representatives of Gram-negative bacteria, and reduced Akkermansia muciniphila in the fecal samples of IL-17RA^−/− mice fed the HFD. Together, these data indicate that the IL-17/IL-17R axis drives intestinal neutrophil migration, limits gut dysbiosis and attenuates LPS translocation to VAT, resulting in protection to MetS.     

Resveratrol inhibits the development of obesity-related osteoarthritis via the TLR4 and PI3K/Akt signaling pathways

ABSTRACT

Aim of the study: Obesity leads to mild, chronic inflammation which is a primary risk factor for osteoarthritis (OA). Resveratrol exerts a protective effect on OA through its anti-inflammatory properties, but the precise mechanism remains unknown. The present study aimed to investigate the mechanism by which resveratrol alleviates obesity-related OA, and whether it is linked to the TLR4 and PI3K/Akt signaling pathways.

Materials and methods: C57BL/6J male mice were fed a high-fat diet (HFD) with or without resveratrol treatment and knee joints were collected for analysis. In addition, IL-1β-induced SW1353 cells were used to study in vitro the reciprocal effects of TLR4 and PI3K/Akt pathways.

Results: Resveratrol inhibited the development of OA in mice fed a HFD. TLR4 and PI3K/Akt signaling pathways were both activated in the articular cartilage; resveratrol treatment down-regulated TLR4 but up-regulated PI3K/Akt signaling. Further in vitro results showed that the effect of resveratrol alone on activation of PI3K/Akt was attenuated but not abolished by the TLR4 inhibitor CLI-095, and resveratrol failed to reduce TLR4 protein expression in IL-1β stimulated cells pretreated with the PI3K inhibitor LY294002.

Conclusions: Resveratrol may exert an anti-osteoarthritic effect by inhibiting TLR4 via the activation of PI3K/Akt signaling pathways. Resveratrol has potential as a drug for OA prevention.     

Porphyromonas gingivalisvirulence in a murine lesion model: effects of immune alterations

This study utilized various mouse strains with documented alterations in immune system components to assess their contribution to modify the virulence ofPorphyromonas gingivalis. P. gingivalisW50 was cultivated on blood agar plates, harvested and used to challenge mice by subcutaneous injection on the dorsolateral surface of the back. Soft tissue lesion development was estimated by measuring the area of the spreading lesion formed by this microorganism over a period of 15 days. Challenge of various normal inbred and outbred mouse strains including: BALB/cN, BALB/cJ, BALB/c nu/+, ICR, B10.A(4R), B10.MBR, A/J, C57BL/6J, CBA/CaH, C.B-17/Icv Tacf DF and C3H/HeN with 2×10¹⁰bacteria showed similar lesion size among these strains (400 mm²). Genetically deficient mouse strains [C.B-17/Icr Tac (SCID); DBA/2 (C5 deficient); BALB/c nu/nu (T cell deficient); CBA/CaHN-XID/J (B cell deficient) and C3H/HeJ (LPS hyporesponsive)] demonstrated a lesion size which was similar to normal animals. C57BL/6J-BgJ (NK cell deficient) mice exhibited a significantly more severe lesion than the other strains tested. Following healing of the lesions, we initiated a secondary infection of the surviving animals to estimate the acquisition of protective immunity following recovery from the primary infection. Normal mice demonstrated a delayed onset and decrease in lesion size of 15 to 30% compared with the primary infection. In contrast, each of the immunodeficient strains appeared unable to develop immune protection to the secondary challenge. The findings suggest that protection against primary infections withP. gingivalisare mediated by innate immune mechanisms (PMN. NK cells). Additionally, it appears that T-cell-dependent humoral responses are critical to developing immunity to subsequentP. gingivalisinfection.     

一种建立小鼠2型糖尿病心肌病模型的方法

目的:采用连续喂养高脂饮食(high-fat diet,HFD)结合单次腹腔注射链脲佐菌素(streptozotocin,STZ)的方法建立小鼠2型糖尿病心肌病模型。方法:将40只5~6周龄C57BL/6J雄性小鼠随机分成2组(每组各20只):对照(control)组,持续以普通饲料喂养;HFD+STZ组,持续以HFD喂养,并于造模第5周注射STZ(100mg/kg)。于造模实验开始(第0周)、第5周、第6周、第11周和第16周,测量体重和血糖,并于第11周和第16周分别对control组和HFD+STZ组小鼠进行心功能检测、胰岛素水平检测、组织学观察和心肌细胞凋亡分析。结果:造模过程中HFD+STZ组小鼠各时期的体重均大于control组(P0.05),注射完STZ后小鼠体重略有下降,但仍高于control组。注射STZ 1周后,HFD+STZ组小鼠空腹血糖值均持续高于13.89 mmol/L。在造模第11周和16周时,HFD+STZ组小鼠胰岛素水平与control组相比均有降低(P0.05)。心功能检测、组织学观察和心肌细胞凋亡分析显示,造模第11周时,HFD+STZ组小鼠的超声、心肌细胞面积和凋亡率等指标与control组相比变化不明显;造模第16周,HFD+STZ组小鼠出现心室功能障碍,心肌细胞肥大,心肌细胞的面积和心肌细胞凋亡率明显大于control组(P0.05)。结论:采用连续喂养HFD结合单次注射STZ可成功建立小鼠2型糖尿病心肌病模型。     

Differences in innate immune responses correlate with differences in murine susceptibility to Chlamydia muridarum pulmonary infection

We investigated the phenotypic basis for genetically determined differences in susceptibility and resistance to Chlamydia muridarum pulmonary infection using BALB/c and C57BL/6 mice. Following C. muridarum intranasal inoculation, the intensity of infection was very different between BALB/c and C57BL/6 beginning as early as 3 days post‐infection. Intrapulmonary cytokine patterns also differed at early time‐points (days 2 and 4) between these two strains of mice. The early recruitment of neutrophils to lung tissue was greater in BALB/c than in C57BL/6 mice and correlated with a higher number of inclusion forming units (IFU) of C. muridarum. At day 12 post‐infection, BALB/c mice continued to demonstrate a greater burden of infection, significantly higher lung cytokine levels for tumour necrosis factor‐α and interleukin‐17 (IL‐17) and a significantly lower level for interferon‐γ than did C57BL/6 mice. In vitro, bone‐marrow‐derived dendritic cells (BMDCs) from BALB/c mice underwent less functional maturation in response to C. muridarum infection than did BMDCs from C57BL/6 mice. The BMDCs of BALB/c mice expressed lower levels of activation markers (CD80, CD86, CD40 and major histocompatibility complex class II) and secreted less IL‐12 and more IL‐23 than BMDCs from C57BL/6 mice. Overall, the data demonstrate that the differences exhibited by BALB/c and C57BL/6 mice following C. muridarum pulmonary infection are associated with differences in early innate cytokine and cellular responses that are correlated with late differences in T helper type 17 versus type 1 adaptive immune responses.     

An improved mouse model that rapidly develops fibrosis in non‐alcoholic steatohepatitis

Non‐alcoholic steatohepatitis (NASH) is a progressive fibrotic disease, the pathogenesis of which has not been fully elucidated. One of the most common models used in NASH research is a nutritional model where NASH is induced by feeding a diet deficient in both methionine and choline. However, the dietary methionine‐/choline‐deficient model in mice can cause severe weight loss and liver atrophy, which are not characteristics of NASH seen in human patients. Exclusive, long‐term feeding with a high‐fat diet (HFD) produced fatty liver and obesity in mice, but the HFD for several months did not affect fibrosis. We aimed to establish a mouse model of NASH with fibrosis by optimizing the methionine content in the HFD. Male mice were fed a choline‐deficient, L‐amino acid‐defined, high‐fat diet (CDAHFD) consisting of 60 kcal% fat and 0.1% methionine by weight. After 1–14 weeks of being fed CDAHFD, the mice were killed. C57BL/6J mice maintained or gained weight when fed CDAHFD, while A/J mice showed a steady decline in body weight (of up to 20% of initial weight). In both strains of mice, plasma levels of alanine aminotransferase increased from week 1, when hepatic steatosis was also observed. By week 6, C57BL/6J mice had developed enlarged fatty liver with fibrosis as assessed by Masson's trichrome staining and by hydroxyproline assay. Therefore, this improved CDAHFD model may be a mouse model of rapidly progressive liver fibrosis and be potentially useful for better understanding human NASH disease and in the development of efficient therapies for this condition.     

Api6在高脂高胆固醇饮食引起肺部炎症中所发挥作用的研究*

 目的：研究凋亡抑制因子6（Api6）在高脂高胆固醇饮食所致C57BL/6J小鼠肺部炎症反应中的作用。方法：6～8周龄的C57BL/6J雄性小鼠喂养于SPF环境中,随机分成2组,分别给予普通饮食和高脂高胆固醇饮食喂养。喂养16周后收集肺组织并采用免疫组织化学和ELISA法鉴定肺组织的炎症状态。实时定量PCR和Western blotting鉴定Api6 mRNA与蛋白的表达水平,流式细胞术检测小鼠支气管肺泡灌洗液细胞凋亡情况。体外培养巨噬细胞RAW264.7,流式细胞术检测Api6对氧化型低密度脂蛋白（oxLDL）引起的细胞凋亡的影响。结果：高脂高胆固醇饮食喂养小鼠16周后,C57BL/6J小鼠肺组织出现以巨噬细胞蓄积以及肿瘤坏死因子α和单核细胞趋化蛋白1升高为主的炎症反应。与普通饮食组相比,高脂高胆固醇饮食喂养小鼠肺组织的Api6 mRNA和蛋白表达水平都显著上调（P<0.01）,同时支气管肺泡灌洗液中的巨噬细胞凋亡水平明显下降（P<0.01）。体外实验证实500 μg/L的重组Api6处理RAW264.7细胞可显著抑制oxLDL引起的细胞凋亡（P<0.05）。结论：高脂高胆固醇饮食可致C57BL/6J小鼠肺组织巨噬细胞蓄积,其机制可能与Api6抑制巨噬细胞的凋亡有关。     

Retrospectively gated MRI for in vivo assessment of endothelium‐dependent vasodilatation and endothelial permeability in murine models of endothelial dysfunction

Endothelial dysfunction is linked to impaired endothelial‐dependent vasodilatation and permeability changes. Here, we quantify both of these phenomena associated with endothelial dysfunction by MRI in vivo in mice. Endothelial function was evaluated in the brachiocephalic artery (BCA) and left carotid artery (LCA) in ApoE/LDLR^?/? and high‐fat diet (HFD)‐fed mice as compared with control mice (C57BL/6J). The 3D IntraGate® FLASH sequence was used for evaluation of changes in vessels’ cross‐sectional area (CSA) and volume following acetylcholine (Ach) administration. Evaluation of endothelial permeability after administration of contrast agent (Galbumin, BioPAL) was based on the variable flip angle method for the assessment of parameters based on the relaxation time (T₁) value. In order to confirm the involvement of nitric oxide (NO) in response to Ach, L‐NAME‐treated mice were also analyzed. To confirm that endothelial permeability changes accompany the impairment of Ach‐dependent vasodilatation, permeability changes were analyzed in isolated, perfused carotid artery. In C57BL/6J mice, Ach‐induced vasodilatation led to an approximately 25% increase in CSA in both vessels, which was temporarily dissociated from the effect of Ach on heart rate. In ApoE/LDLR^?/? or HFD‐fed mice Ach induced a paradoxical vasoconstriction that amounted to approximately 30% and 50% decreases in CSA of BCA and LCA respectively. In ApoE/LDLR^?/? and HFD‐fed mice endothelial permeability in BCA was also increased (fall in T₁ by about 25%). In L‐NAME‐treated mice Ach‐induced vasodilatation in BCA was lost. In isolated, perfused artery from ApoE/LDLR^?/? mice endothelial permeability was increased. MRI‐based assessment of endothelium‐dependent vasodilatation induced by Ach and endothelial permeability using a retrospectively self‐gated 3D gradient‐echo sequence (IntraGate® FLASH) enables the reliable detection of systemic endothelial dysfunction in mice and provides an important tool for the experimental pharmacology of the endothelium in murine models of diseases in vivo. Copyright © 2016 John Wiley & Sons, Ltd.     

Tanshinone IIA Attenuates Atherosclerosis in Apolipoprotein E Knockout Mice Infected with <Emphasis Type="Italic">Porphyromonas gingivalis</Emphasis>

Tanshinone IIA (TSA), a pharmacologically active component isolated from Danshen, may prevent cardiovascular diseases due to its anti-inflammatory, anti-oxidative, and anti-adipogenic effects. Porphyromonas gingivalis, a major periodontal pathogen, may contribute to the progression of atherosclerosis. Here, we studied the effects of TSA on atherosclerosis in ApoE^?/? mice with P. gingivalis infection. Eight-week-old ApoE^?/? mice were randomized to (a) phosphate-buffered saline (PBS), (b) P. gingivalis, and (c) P. gingivalis + TSA (60 mg kg^?1 day^?1). The mice were injected with (a) PBS, or (b) and (c) P. gingivalis 3 times per week for a total of 10 times. After 8 weeks, atherosclerotic risk factors in serum and in heart, aorta, and liver tissues were analyzed in all mice using Oil Red O, atherosclerosis cytokine antibody arrays, enzyme-linked immunosorbent assay (ELISA), real-time PCR, and microRNA array. CD40, G-CSF, IFN-γ, interleukin (IL)-1β, IL-6, MCP-1, MIP-3α, tumor necrosis factor-α (TNF-α), and VEGF were attenuated by TSA in atherosclerosis cytokine antibody arrays. TSA-treated mice showed a significant reduction of C-reactive protein (CRP), ox-LDL, IL-1β, IL-6, IL-12, and TNF-α in ELISA data. Real-time PCR analyses showed that TSA decreased the expression of CCL-2, CD40, IL-1β, IL-6, TNF-α, and MMP-2 in heart and aorta tissues. Moreover, hepatic CRP was downregulated by TSA, although FASN and HMG-CoA were not. The relative expressions of miR-146b and miR-155 were elevated by P. gingivalis infection and were downregulated by TSA treatment. These results suggest that TSA was a potential therapeutic agent that may have the ability to prevent P. gingivalis-induced atherosclerosis associated with anti-inflammatory and anti-oxidative effects.     

Whole-Body Vibration Training Effect on Physical Performance and Obesity in Mice

The purpose of this study was to verify the beneficial effects of whole-body vibration (WBV) training on exercise performance, physical fatigue and obesity in mice with obesity induced by a high-fat diet (HFD). Male C57BL/6 mice were randomly divided into two groups: normal group (n=6), fed standard diet (control), and experimental group (n=18), fed a HFD. After 4-week induction, followed by 6-week WBV of 5 days per week, the 18 obese mice were divided into 3 groups (n=6 per group): HFD with sedentary control (HFD), HFD with WBV at relatively low-intensity (5.6 Hz, 0.13 g) (HFD+VL) or high-intensity (13 Hz, 0.68 g) (HFD+VH). A trend analysis revealed that WBV increased the grip strength in mice. WBV also dose-dependently decreased serum lactate, ammonia and CK levels and increased glucose level after the swimming test. WBV slightly decreased final body weight and dose-dependently decreased weights of epididymal, retroperitoneal and perirenal fat pads and fasting serum levels of alanine aminotransferase, CK, glucose, total cholesterol and triacylglycerol. Therefore, WBV could improve exercise performance and fatigue and prevent fat accumulation and obesity-associated biochemical alterations in obese mice. It may be an effective intervention for health promotion and prevention of HFD-induced obesity.     

Failure of P strain mice to respond to vaccination against schistosomiasis correlates with impaired production of IL-12 and up-regulation of Th2 cytokines that inhibit macrophage activation

In contrast to most inbred strains, P mice fail to develop significant resistance to Schistosoma mansoni infection as a result of vaccination with either radiation-attenuated cercariae or schistosome antigens plus Bacillus Calmette Guérin, and this failure correlates with defects in macrophage larvicidal activity. Supernatant fluids from antigen-treated in vitro cultures of splenocytes from vaccinated P mice demonstrate less macrophage stimulatory activity than do supernatants from cells of vaccine-responsive strains such as C57BL/6. This is not due either to diminished production of the macrophage-activating cytokine IFN-γ by P mice, or to a lesser responsiveness of macrophages from P mice to activation by IFN-γ. Rather, P splenocytes produce two-to threefold higher amounts of IL-4 and IL-10, cytokines which down-regulate the cytotoxic potential of IFN-γ-treated macrophages. Thus, the macrophage-activating potential of cytokine preparations from vaccinated P mice can be completely recovered by in vitro treatment with antibodies to IL-4 or IL-10. Moreover, lower levels of IL-12, a cytokine involved in promoting development of Th1 responses, are produced by splenocytes from P mice as compared to C57BL/6 counterparts. These studies indicate that a genetic predisposition toward an impaired production of IL-12 and an increased production of down-regulatory Th2 cytokines correlate with low response to vaccination against S. mansoni.     

载脂蛋白E基因敲除小鼠动脉粥样硬化早期血管外膜成纤维细胞增殖活性增强

目的:探讨动脉外膜成纤维细胞增殖与早期动脉粥样硬化病灶形成的关系。方法:选择6周龄载脂蛋白E基因敲除[apoE(-/-)]小鼠和野生型C57BL/6小鼠,高脂喂养2、4和10周后,在各个时点处死动物前24 h经腹腔注射5-溴-2-脱氧尿嘧啶(BrdU),后选取升主动脉制备连续切片,通过HE染色观察组织形态学的变化,用免疫组化方法观察不同时点血管外膜及内膜BrdU的表达变化。体外培养高脂喂养2周的apoE(-/-)小鼠和C57BL/6小鼠动脉外膜成纤维细胞,通过BrdU掺入法测定细胞增殖活性,流式细胞术测定细胞周期。结果:体内实验发现apoE(-/-)小鼠高脂喂养2周后,在无可见内膜病灶形成之前,首先在主动脉外膜发现BrdU标记的阳性细胞,之后才在损伤内膜观察到BrdU标记细胞。而C57BL/6小鼠在任何时点都未检测到BrdU标记的细胞。体外实验观察到apoE(-/-)小鼠血管外膜成纤维细胞BrdU标记的细胞数显著多于C57BL/6小鼠(P0.01),apoE(-/-)小鼠血管外膜成纤维细胞S期及G2/M期所占百分比明显高于对照组(P0.05)。结论:血管外膜成纤维细胞增殖可能参与早期动脉粥样硬化病灶形成。     

FAT/CD36在高脂喂养小鼠脂肪组织炎症中的作用

目的:探讨脂肪酸转运酶/白细胞分化抗原36(fatty acid translocase/CD36,FAT/CD36)在高脂饮食诱导的小鼠脂肪组织炎症中的作用。方法:将6周龄雄性C57BL/6J小鼠分别随机分为普通饮食组和高脂饮食组,喂养14周后,ELISA测定血清游离脂肪酸(FFA)含量,应用荧光实时定量PCR和Western blotting检测脂肪组织中FAT/CD36及炎症/趋化因子(IL-1β、IL-6、TNF-α、MCP-1、MIP-1)mRNA和蛋白的表达,免疫组织化学染色检测脂肪组织巨噬细胞浸润,比较高脂喂养14周的野生型小鼠和CD36基因敲除小鼠的脂肪组织炎症反应情况。结果:与普通饮食组相比,高脂饮食能增强C57BL/6J小鼠脂肪组织的FAT/CD36及炎症/趋化因子的表达,促进巨噬细胞在脂肪组织的浸润。与高脂饮食喂养的野生型小鼠相比,CD36基因敲除小鼠的脂肪组织炎症因子、趋化因子表达明显降低,脂肪组织巨噬细胞浸润减少。结论:高脂饮食通过上调脂肪组织FAT/CD36的表达激活了脂肪组织炎症。     

The beneficial effects of 18β-glycyrrhetinic acid on the experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mouse model

Aim: The aim of this study was to investigate the beneficial effects of 18β-glycyrrhetinic acid (GA) on the experimental allergic encephalomyelitis (EAE) in C57BL/6 mice. GA is a natural substance found in the root of licorice and is used in traditional Chinese medicine. It has many pharmacological activities such as antioxidant, anti-inflammatory, and anti-cancer effects.

Materials and methods: A total of 40 C57BL/6 mice were divided equally into four groups: (1) Control, (2) EAE, (3) GA and (4) GA?+?EAE. 14?days after induction of EAE with MOG35-55 and pertussis toxin, mice were treated with GA at doses of 100?mg/kg/day for 7?days intraperitoneally.

Results: To our results, oxidative stress and lipid peroxidations (elevated TBARS levels, decreased GPx, SOD, CAT, and GSH levels) were significantly (p?p?≤?.01) and cytokine levels (TNF-α and IL-1β, p?p?Conclusions: In conclusion, the GA treatment can protect the brain tissue against EAE in mice with its antioxidant and anti-inflammatory properties.     

The central adaptor molecule TRIF influences L. sigmodontis worm development

Worldwide approximately 68 million people are infected with lymphatic filariasis (Lf), provoked by Wuchereria bancrofti, Brugia malayi and Brugia timori. This disease can lead to massive swelling of the limbs (elephantiasis) and disfigurement of the male genitalia (hydrocele). Filarial induced immune regulation is characterised by dominant type 2 helper T cell and regulatory immune responses. In vitro studies have provided evidence that signalling via Toll-like receptor-mediated pathways is triggered by filarial associated factors. Nevertheless, until now, less is known about the role of the adapter molecule TRIF during in vivo infections. Here, we used the rodent-specific nematode Litomosoides sigmodontis to investigate the role of TLR signalling and the corresponding downstream adapter and regulatory molecules TRIF, MyD88, IRF1 and IRF3 during an ongoing infection in semi-susceptible C57BL/6 mice. Interestingly, lack of the central adapter molecule TRIF led to higher worm burden and reduced overall absolute cell numbers in the thoracic cavity (the site of infection) 30 days post-infection. In addition, frequencies of macrophages and lymphocytes in the TC were increased in infected TRIF^−/− C57BL/6 mice, whereas frequencies of eosinophils, CD4⁺ and CD8⁺ T cells were reduced. Nevertheless, cytokine levels and regulatory T cell populations remained comparable between TRIF-deficient and wildtype C57BL/6 mice upon 30 days of L. sigmodontis infection. In summary, this study revealed a crucial role of the adapter molecule TRIF on worm recovery and immune cell recruitment into the site of infection 30 days upon L. sigmodontis infection in C57BL/6 mice.

     

Parasitic Nematode-Induced Modulation of Body Weight and Associated Metabolic Dysfunction in Mouse Models of Obesity

Obesity is associated with a chronic low-grade inflammation characterized by increased levels of proinflammatory cytokines that are implicated in disrupted metabolic homeostasis. Parasitic nematode infection induces a polarized Th2 cytokine response and has been explored to treat autoimmune diseases. We investigated the effects of nematode infection against obesity and the associated metabolic dysfunction. Infection of RIP2-Opa1KO mice or C57BL/6 mice fed a high-fat diet (HFD) with Nippostrongylus brasiliensis decreased weight gain and was associated with improved glucose metabolism. Infection of obese mice fed the HFD reduced body weight and adipose tissue mass, ameliorated hepatic steatosis associated with a decreased expression of key lipogenic enzymes/mediators, and improved glucose metabolism, accompanied by changes in the profile of metabolic hormones. The infection resulted in a phenotypic change in adipose tissue macrophages that was characterized by upregulation of alternative activation markers. Interleukin-13 (IL-13) activation of the STAT6 signaling pathway was required for the infection-induced attenuation of steatosis but not for improved glucose metabolism, whereas weight loss was attributed to both IL-13/STAT6-dependent and -independent mechanisms. Parasitic nematode infection has both preventive and therapeutic effects against the development of obesity and associated features of metabolic dysfunction in mice.