Activation Of Innate Immune System Research Articles

Behavioral responses of mGluR3-KO mice to the lipopolysaccharide-induced innate inflammatory reaction

Acute lipopolysaccharide (LPS) administration induces innate inflammatory signalling and produces sickness reaction characterized by reduced drinking, eating and reduced locomotor exploration, as well as emotional changes indicating increased helplessness/despair. LPS administration has been used to model behavioral and emotional responses to inflammatory reactions. Our aim was to find out whether the lack of metabotropic glutamate receptor 3 (mGluR3) in the knockout (KO) mice affects behavioral effects of LPS in vivo, as mGluR3 may have a role in inflammatory signalling. After LPS (1 mg/kg, i.p.) administration, we compared wild-type (WT) and mGluR3-KO mice for differences in gross appearance and locomotion at 3- and 6-h time points, anxiety-like behavior in the light-dark test at 24-h, depression-like behavior in the tail-suspension test at 25-h, and in the forced-swim test at 48-h time points. Body weight and water consumption were monitored. Based on behavioral scorings at the 3-h and 6-h time points, the mGluR3-KO mice reacted to LPS in a similar way as the WT mice. LPS-induced reductions in the body weight or water consumption did not differ between genotypes. Interestingly, LPS-induced reductions in the body temperature were significantly enhanced in male and female mGluR3-KO mice at 6-h and 3-h time points, respectively. In the light-dark anxiety-test the saline-treated mGluR3-KOs showed increased anxiolytic-like behaviors compared to the saline-treated WT mice. LPS treatment significantly reduced the KO entries to the light compartment to the same level as WT mice given saline. Total locomotion was significantly reduced in both genotypes by LPS. In the despair models, no genotype difference was observed after saline or LPS, neither had LPS treatment any significant effect on immobility. Although changes in glutamatergic neurotransmission may partly mediate effects of systemic LPS administration, mGluR3 appears not to be crucial in behavioral responses to acute activation of innate immune system.

The fit of codon usage of human-isolated avian influenza A viruses to human

Avian influenza A viruses (AIVs) classify into 18 hemagglutinin (HA) and 11 neuraminidase (NA) subtypes. Even though H1N1 and H3N2 subtypes usually circulate among humans leading to infection, occasionally, H5, H6, H7, H9, and H10 that circulate in poultry also infect humans, and especially H5N1 and H7N9. Efficient virus replication is a critical factor that influences infection. Codon usage of a virus must coevolve with its host for efficient viral replication, therefore, we conduct a comprehensive analysis of codon usage bias in human-isolated AIVs to test their adaptation to host expression system. The relative synonymous codon usage (RSCU) pattern, and the codon adaptation index (CAI) are calculated for this purpose. We find that all human-isolated AIVs tend to eliminate GC and CpG compositions, which may prevent activation of the host innate immune system. Although codon usage differs between AIV subtypes, our data support the conclusion that natural selection has played a major role and mutation pressure a minor role in shaping codon usage bias in all AIVs. Our efforts discover that codon usage of genes encoding surface proteins of H5N1, and the polymerase genes of H7N9 has better fit to the human expression system. This may associate with their better replication and infection in human.

Epilepsy and Alterations of the Blood-Brain Barrier: Cause or Consequence of Epileptic Seizures or Both?

The blood-brain barrier (BBB) is a dynamic, highly selective barrier primarily formed by endothelial cells connected by tight junctions that separate the circulating blood from the brain extracellular fluid, thereby preserving a narrow and stable homeostatic control of the neuronal environment. The endothelial cells lining the brain microvessels are under the inductive influence of neighboring cell types within the "neurovascular unit" including astrocytes and pericytes. In addition to the morphological characteristics of the BBB, various specific transport systems, enzymes, and receptors regulate the molecular and cellular traffic across the barrier. Furthermore, the intact BBB prevents many macromolecules and immune cells from entering the brain. This changes dramatically following epileptogenic brain insults; such insults, among other BBB alterations, lead to albumin extravasation and diapedesis of leukocytes from blood into brain parenchyma, inducing or contributing to epileptogenesis, which finally leads to development of spontaneous recurrent seizures and epilepsy. Furthermore, seizures themselves may cause BBB disruption with albumin extravasation, which has been shown to be associated with activation of astrocytes, activation of innate immune systems, and modifications of neuronal networks. However, seizure-induced BBB disruption is not necessarily associated with enhanced drug penetration into the brain, because the BBB expression of multidrug efflux transporters such as P-glycoprotein increases, most likely as a "second line defense" mechanism to protect the brain from drug toxicity. Hopefully, a better understanding of the complex BBB alterations in response to seizures and epilepsy can lead to novel therapeutic intervention to prevent epileptogenesis and the development of other detrimental sequelae of brain injury.

Paramagnetic Rims in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder: A Quantitative Susceptibility Mapping Study with 3-T MRI.

Background and PurposeIron retained by activated microglia and macrophages in multiple sclerosis (MS) lesions may serve as a marker of innate immune system activation. Among several magnetic resonance imaging (MRI) methods, there has been recent interest in using quantitative susceptibility mapping (QSM) as a potential tool for assessing iron levels in the human brain. This study examined QSM findings in MS and neuromyelitis optica spectrum disorder (NMOSD) lesions obtained with 3-T MRI to assess imaging characteristics related to paramagnetic rims around brain lesions in MS and NMOSD.MethodsThis study included 32 MS and 21 seropositive NMOSD patients. MRI images were obtained using two 3-T MRI devices (Ingenia, Philips Healthcare; and Magnetom Verio, Siemens Healthineers) during routine diagnosis and treatment procedures. Multi and single echo gradient echo magnitude and phase images were obtained for QSM reconstruction. QSM images were used to characterize the detected lesions, and the findings were compared between MS and NMOSD.ResultsTotals of 71 and 35 MRI scans were performed during the study period in MS and NMOSD patients, respectively. In QSM images, paramagnetic rims were found in 26 (81.2%) MS patients and 1 (4.8%) NMOSD patient. Eight of the 22 MS patients and only 1 of the 10 NMOSD patients who underwent follow-up MRI showed new paramagnetic rims. The paramagnetic rim lesions appeared after enhancement or in new T2-weighted lesions without enhancement.ConclusionsParamagnetic rims might be a characteristic MRI finding for MS, and therefore they have potential as an imaging marker for differentially diagnosing MS from NMOSD using 3-T MRI.

FMF Is Associated With a Wide Spectrum of MHC Class I- and Allied SpA Disorders but Not With Classical MHC Class II-Associated Autoimmune Disease: Insights From a Large Cohort Study.

Objectives: To test the hypothesis that familial Mediterranean fever (FMF)-associated autoinflammation may exaggerate the tendency toward adaptive immunopathology or spondyloarthritis (SpA)-associated disorders including major histocompatibility complex (MHC) class I associated disorders but not classical MHC class II-associated disorders that exhibit transplacental autoimmunity including myasthenia gravis and pemphigus.Methods: Seven thousand seven hundred forty-seven FMF patients and 10,080 age- and sex-matched controls in the Clalit Health Services medical database were identified and compared in terms of prevalence of SpA-associated disorders. We also evaluated four classical and strong MHC class II-associated disorders, namely, pemphigus vulgaris, myasthenia gravis, sarcoidosis, and pernicious anemia, to ascertain whether such associations with SpA-spectrum disease were specific or merely reflected the non-specific consequences of innate immune system activation on driving divergent types of immunity. The diagnosis of FMF was based on the medical records and not genetically proven.Results: FMF showed a strong association with MHC class I-related diseases: odds ratio (OR) of 28.58 [95% confidence interval (95% CI), 6.93–117.87; p < 0.0001] for Behçet's disease, OR of 10.33 (95% CI, 4.09–26.09; p < 0.0001) for ankylosing spondylitis, and OR of 1.67 (95% CI, 1.19–2.33; p = 0.0029) for psoriasis. For weakly MHC class I-linked diseases, an OR of 3.76 (95% CI, 2.48–5.69; p < 0.0001) for Crohn's disease and OR of 2.64 (95% CI, 1.52–4.56; p = 0.0005) for ulcerative colitis were found. No association was found between FMF and the four MHC class II-associated autoimmune disorders.Conclusion: FMF patients are associated with increased risk of SpA-related disease diagnosis including MHC-I-opathies but not MHC-II-associated autoimmune diseases, suggesting that tissue-specific dysregulation of innate immunity share between FMF and SpA spectrum disorders may drive adaptive immune MHC class I-associated conditions.

P3489Endothelial adenosine-to-inosine RNA editing is indispensable for vascular integrity

Abstract Background Adenosine (A)-to-inosine (I) RNA editing is a powerful upstream regulator of double-stranded RNA (dsRNA) metabolism, its role however in tissue homeostasis remains poorly understood. We have recently reported that RNA editing is dysregulated in human atherosclerotic heart disease, although its role in the maintenance of endothelial cell (EC) function is unknown. Purpose The goal of the present study is to evaluate the role of EC-specific ADAR1 in vascular homeostasis in vivo. Methods Constitutional or inducible EC restricted ADAR1 ablation was achieved by crossing mice carrying a conditional (floxed) ADAR1 allele with either a Tie2-Cre or with a tamoxifen-inducible Cdh5-CreERT2 mouse line. EC function was assessed by the postnatal retinal angiogenesis model and barrier function assays and immunohistochemistry of lung and liver tissues. Cell culture assays, gene-silencing techniques, RT-qPCR, western blot and confocal microscopy were utilized to assess the ADAR1 effects in intracellular endothelial signalling. Results Constitutive endothelial ADAR1 ablation caused prenatal lethality at embryonic stage E13.5, demonstrating an essential role for endothelial ADAR1 in development. Postnatal ADAR1 ablation resulted in reduced vascular outgrowth, reduced vessel branching in the central vascular plexus and decreased filopodial protrusions from ECs at the angiogenic front of the vascular plexus compared with littermate control mice at P5. Furthermore, endothelial ADAR1 ablation in adult mice resulted in sudden death within 6–8 days after activation of Cre recombinase due to development of severe pleural effusions caused by widespread vascular leakage, indicating a disturbance of EC barrier function in lung microvasculature. Mechanistically, ADAR1-mediated RNA editing is essential for the metabolism of endogenous long-to-short dsRNAs, while silencing of endothelial ADAR1 resulted in accumulation of cytoplasmic long dsRNAs. Long dsRNAs are recognised as a danger-associated molecular pattern by the cytosolic innate immune sensing and signalling sensors. Consequently, the cytoplasmic accumulation of endogenous long dsRNAs resulted in activation of innate immune system in ECs, as assessed by the induction of interferon-β. Concomitantly, activation of the cytoplasmic dsRNA sensors resulted in dissociation of beta-catenin from VE-cadherin in EC junctions and endocytosis of VE-cadherin. Conclusion ADAR1-mediated RNA editing of long dsRNAs is essential for the long-to-short dsRNA metabolism and thus suppression of endogenous innate immune sensing and signalling. EC-restricted ADAR1 ablation results in embryonic lethality, impaired retinal angiogenesis at P5 and sudden death in adult mice due to pleural effusions, which all indicate that ADAR1-mediated RNA editing is indispensable for maintenance of vascular barrier integrity.

EXTRACORPOREAL MEMBRANE SUPPORT AS A BRIDGE TO PULMONARY THROMBOENDARTERECTOMY IN CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION: A NOVEL STRATEGY IN PULMONARY ISCHEMIA-REPERFUSION INJURY

SESSION TITLE: Case Report Semifinalists 5 SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM INTRODUCTION: The description of Ischemia-reperfusion injury (IRI) is first accredited to Dr. R. B. Jennings’ in his 1960 animal study on myocardial necrosis. IRI is initiated by an ischemic or inflammatory injury to the alveolar capillary endothelium activating NADPH oxidase 3 (NOX-3) and inducible Nitric Oxide Synthase (iNOS). Reperfusion and hyperoxia provide substrate for these oxidation reactions to create an oxidative stress environment. IRI can be associated with significant morbidity and mortality following lung transplantation and pulmonary thromboendarterectomy (PTE). We describe a unique case of acute lung injury complicated CTEPH for which V-V ECMO was used as a bridge to PTE to limit IRI. CASE PRESENTATION: A 43-year-old female with known CTEPH presented to an outside hospital with progressive dyspnea, hypoxia and right sided weakness. CT head disclosed left occipital lobe and cerebellar infarcts. Chest CTA showed a chronic complete occlusion of the left pulmonary trunk and acute right segmental and subsegmental thrombi (level 1). An echocardiogram disclosed a PFO and severe right ventricular enlargement. Right heart catheterization (RHC) disclosed severe pulmonary hypertension (mPA 59, wedge 11). A mechanical thrombectomy was unsuccessfully attempted. Patient was transferred for emergent PTE evaluation, however, developed acute hypoxic respiratory failure and was intubated upon arrival. Repeat CT chest disclosed dense right > left organizing infiltrates bibasilar suggestive of acute lung injury. Due to high risk of IRI, PTE was deferred, and patient was bridged to V-V EMCO for ongoing intractable hypoxemia and acute lung injury. I.V. epoprostenol was initiated for medical management for PH. She was decannulated after 2 weeks, however, required intermitted mechanical ventilation and aggressive physical therapy. PTE was successfully performed on hospital day 54 and epoprostenol was immediately discontinued. One-time doses of Lasix 20mg and solumedrol 125mg were given for mild IRI. Tracheostomy was decannulated by postop day 11 and patient was discharged home without oxygen. DISCUSSION: IRI creates tissue injury via superoxide species, capillary hyperpermeability, and activation of innate immune system via downstream proinflammatory chemokines. We present a unique case of acute lung injury in the setting of CTEPH requiring PTE. We utilized V-V ECMO as a bridge to PTE surgery resulting in a two-step strategy to limit IRI:(1)Allowance of adequate recovery from the initial endothelial injury employing supportive measures not excluding pulmonary/circulatory support if necessary;(2)Early proactive management of the inflammatory and capillary leak sequela of IRI as expected known entities after reperfusion. CONCLUSIONS: This strategy allows repletion of antioxidants. Further investigatory studies on this topic will hopefully provide clarity on the efficacy of this strategy. Reference #1: De Perrot M, Liu, M, Waddell TK, Keshavjee S. Ischemia-reperfusion-Induced Lung Injury. American Journal of Respiratory and Critical Care Medicine. 2003;167(4):490-511 Reference #2: Jennings RB, Sommers HM, Smyth GA, Flack HA, Linn H. Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog. Arch Pathol. 1960;70:68–78 Reference #3: Ovechkin AV, Lominadze D, Sedoris KC, Robinson TW, Tyagi SC, Roberts AM. Lung ischemia-reperfusion injury: implications of oxidative stress and platelet-arteriolar wall interactions. Arch Physiol Biochem. 2007;113(1):1-12. DISCLOSURES: No relevant relationships by Tony Hodges, source=Web Response No relevant relationships by Kurt Olson, source=Web Response No relevant relationships by Esa Rayyan, source=Web Response No relevant relationships by Rajeev Saggar, source=Web Response No relevant relationships by Sarika Savajiyani, source=Web Response No relevant relationships by Nafis Shamsid-Deen, source=Web Response No relevant relationships by Gurvijay Singh, source=Web Response No relevant relationships by Ramachandra Sista, source=Web Response No relevant relationships by Steve Tseng, source=Web Response

P4141Lack of IkBNS promotes cholate-containing high-fat diet-induced inflammation and atherogenesis in low-density lipoprotein (LDL) receptor-deficient mice

Abstract Background IκBNS is one of the nuclear IκB proteins and regulates a subset of Toll-like receptor (TLR) dependent genes. LPS acts as extremely strong stimulator of innate immunity. We tried to investigate whether stimulation of innate immunity could promote atherosclerosis in the IκBNS-deficient atherogenic mice. However all IκBNS-deficient mice died of LPS challenge at a dose of which almost all wild-type mice survived, because IκBNS-deficient mice are highly sensitive to LPS-induced endotoxin shock. Then, we decided to use a cholate-containing high fat diet (HFD(CA(+))), which has been widely used as an atherogenic diet in mice. Furthermore, HFD(CA(+)) has been shown to induce TLR4 mediated early inflammatory response. The present study aims to clarify the lack of IκBNS promotes atherogenesis in LDL receptor-deficient (LDLr−/−) mice fed HFD(CA(+)) compared with those fed a cholate-free HFD (HFD(CA(−)). Methods and results Mice that lacked IκBNS (IκBNS−/−) were crossed with LDLr−/− mice and formation of atherosclerotic lesions was analyzed after 6 weeks consumption of HFD(CA(+)) or HFD(CA(−)). The extent of atherosclerosis in the aorta (en face) was significantly increased in IκBNS−/−/LDLr−/−(CA(+)) mice compared with others after 6-week consumption of HFD (p&lt;0.01) (Figure). Interestingly, HFD(CA(−)) did not induce significant atherosclerotic lesions in IκBNS−/−/LDLr−/− compared with LDLr−/− mice after 6-week consumption (Figure). Immunostaining of aortic root lesion revealed that HFD(CA(+)) significantly increased positive area of Mac-3 (macrophage) by 1.5-fold (p=0.01) and TLR4, interleukin-6 (IL-6) expression by 1.7-fold (P&lt;0.05) and 1.5-fold (p&lt;0.05) respectively in IκBNS−/−/LDLr−/− (CA(+)) compared to LDLr−/− (CA(+)) mice. Furthermore, active STAT3 (pSTAT3)-positive cells were significantly increased by 1.7-fold in the atherosclerotic lesions of IκBNS−/−/LDLr−/− (CA(+)) compared with LDLr−/− (CA(+)) mice (p&lt;0.01). TLR4 positive areas, IL-6 positive areas, and pSTAT3 positive cells were overlapped with Mac-3, indicating that TLR4-IL-6-STAT3 axis was activated in macrophages in IκBNS−/−/LDLr−/− (CA(+)) mice. On the other hand, HFD(CA(−)) could not induce any difference in these immunoreactivities of arteriosclerotic lesions between IκBNS−/−/LDLr−/− (CA(−)) compared with LDLr−/− (CA(−)) mice. These findings suggest that IκBNS deficiency and HFD(CA(+)) promote atherogenesis in LDLr−/− mice via TLR4/IL-6/STAT3 pathway. Finally, we show the monocytes from peripheral blood of IκBNS−/−/LDLr−/− (CA(+)) mice were found to contain the most mounts of Ly6Chi among four groups, suggesting that lack of IκBNS enhances inflammation in the response HFD(CA(+)) feeding and thereby influence atherogenesis in IκBNS−/−/LDLr−/− mice. Aortic root atherosclerotic lesions Conclusions The present study is the first to demonstrate that the activation of innate immune system using HFD(CA(+)) induced significant inflammation and atherogenesis in IκBNS−/−/LDLr−/− compared with LDLr−/− mice.

Innate Immune Cells and C-Reactive Protein in Acute First-Episode Psychosis and Schizophrenia: Relationship to Psychopathology and Treatment

Innate immunity has been linked to initiation of Alzheimer’s disease and multiple sclerosis. Moreover, risk of first-episode psychosis (FEP) and schizophrenia (Sz) is increased after various infections in predisposed individuals. Thus, we hypothesized an analogous role of innate immunity with increased C-reactive protein (CRP) in non-affective psychosis. Differential blood count, CRP, neutrophil and monocyte–macrophage activation markers, cortisol and psychotic symptoms (Positive and Negative Syndrome Scale [PANSS]) were assessed in controls (n = 294) and acutely ill unmedicated FEP (n = 129) and Sz (n = 124) patients at baseline and after 6 weeks treatment. Neutrophils, monocytes, and CRP were increased in patients vs controls at baseline (P < .001), and neutrophil and monocyte counts correlated positively with activation markers. Eosinophils were lower at baseline in FEP (P < .001) and Sz (P = .021) vs controls. Differences in neutrophils (P = .023), eosinophils (P < .001), and CRP (P < .001) were also present when controlling for smoking and cortisol, and partially remitted after antipsychotic treatment. FEP patients with high neutrophils (P = .048) or monocytes (P = .021) had higher PANSS-P scores at baseline but similar disease course. CRP correlated with PANSS-P at baseline (ρ = 0.204, P = .012). Improvement of positive symptoms after treatment correlated with declining neutrophils (ρ = 0.186, P = .015) or CRP (ρ = 0.237, P = .002) and rising eosinophils (ρ = −0.161, P = .036). In FEP, normalization of neutrophils (ρ = −0.231, P = .029) and eosinophils (ρ = 0.209, P = .048) correlated with drug dosage. In conclusion, innate immune system activation correlated with PANSS-P, supporting the immune hypothesis of psychosis. Neutrophil and monocyte counts and CRP levels may be useful markers of disease acuity, severity, and treatment response.

Cutibacterium acnes phylotypes diversity loss: a trigger for skin inflammatory process

Acne has long been understood as a multifactorial chronic inflammatory disease of the pilosebaceous follicle, where Cutibacterium acnes (subdivided into six main phylotypes) is a crucial factor. In parallel, the loss of microbial diversity among the skin commensal communities has recently been shown as often accompanied by inflammatory skin disorders. This study investigated the association of C.acnes phylotype diversity loss and the impact on Innate Immune System (IIS) activation. The IIS response of skin after incubation with phylotypes IA1, II or III individually and with the combination of IA1+II+III phylotypes, was studied in an in vitro skin explant system. The inflammatory response was monitored by immunohistochemistry and ELISA assays, targeting a selection of Innate Immune Markers (IIMs) (IL-6, IL-8, IL-10, IL-17, TGF-β). IIMs were significantly upregulated in skin when being incubated with phylotype IA1 alone compared with the combination IA1+II+III. In parallel, ELISA assays confirmed these results in supernatants for IL-17, IL-8 and IL-10. We identify the loss of C.acnes phylotype diversity as a trigger for IIS activation, leading to cutaneous inflammation. These innovative data underline the possibility to set up new approaches to treat acne. Indeed, maintaining the balance between the different phylotypes of C.acnes may be an interesting target for the development of drugs.

Hyperuricemia is associated with impaired intestinal permeability in mice.

Hyperuricemia is associated with many metabolic diseases. However, the underlying mechanism remains unknown. The gut microbiota has been demonstrated to play significant roles in the immunity and metabolism of the host. In the present study, we constructed a hyperuricemic mouse model to investigate whether the metabolic disorder caused by hyperuricemia is related to intestinal dysbiosis. A significantly increased intestinal permeability was detected in hyperuricemic mice. The difference in microflora between wild-type and hyperuricemic mice accompanies the translocation of gut microbiota to the extraintestinal tissues. Such a process is followed by an increase in innate immune system activation. We observed increased LPS and TNF-α levels in the hyperuricemic mice, indicating that hyperuricemic mice were in a state of low-grade systemic inflammation. In addition, hyperuricemic mice presented early injury of parenteral tissue and disordered lipid metabolism. These findings suggest that intestinal dysbiosis due to an impaired intestinal barrier may be the key cause of metabolic disorders in hyperuricemic mice. Our findings should aid in paving a new way of preventing and treating hyperuricemia and its complications.NEW & NOTEWORTHY Hyperuricemia is associated with many metabolic diseases. However, the underlying mechanism remains unknown. We constructed a hyperuricemic mouse model to explore the relationship between intestinal dysbiosis and metabolic disorder caused by hyperuricemia.

PROSPECTS OF Toll-LIKE RECEPTOR AGONISTS AND ANTAGONISTS FOR PREVENTION AND TREATMENT OF VIRAL INFECTIONS

Antiviral research has focused mainly on viral targets. However, cellular targets involved in the viral life cycle and antiviral response are becoming more attractive for research, providing a variety of opportunities for antiviral therapy. Toll-like receptors (TLR) play an important role in activation of both innate and adaptive immune systems, including a response to respiratory viral infections. In this review we shall discuss TLRs as potential targets for development of novel antiviral drugs including the mechanisms for induction the antiviral response by means of type I interferon production, as well as viral evasion strategies. In addition, we describe several new molecules that have been applied as TLR agonists or antagonists. The safety issues are also discussed.

Dendritic cells in the pathogenesis of viral hepatitis C

Infection with hepatitis C virus (HCV) is a public health problem; it establishes a chronic course in most (up to 85%) infected patients and increases the risk for developing liver cirrhosis, hepatocellular carcinoma, and severe extrahepatic manifestations. The mechanisms of HCV persistence are largely related to the inefficient antiviral response of the host immune system. The effective clearance of the virus requires early activation of innate immune system together with the induction of a strong multiepitopic adoptive T cell response and long-term antiviral memory. Dendritic cells (DCs), which represent a heterogeneous population of antigen-presenting cells, contribute to the production of type I interferon, activate natural killer cells and induce adoptive immune response thus playing a major role in antiviral defense. In this case, DCs dysfunction in HCV-infection is considered to be the one of the mechanism that allows the virus to escape from the immune surveillance. The present review includes current data focusing on the role of DCs in the anti-HCV immune response and highlights a number of key issues related to the phenotypic and functional changes of various DC subpopulations in HCV-infection, the mechanisms of DC impairments and the prospects for treatment of chronic hepatitis C based on the use of ex vivo generated DCs.

Comparison of TLR2/1, NF-кB p105/50, NF-кB p65, and TNF-α expressions in the macrophages between multibacillary leprosy patients with and without erythema nodosum leprosum signifying innate immune system activity

Comparison of TLR2/1, NF-кB p105/50, NF-кB p65, and TNF-α expressions in the macrophages between multibacillary leprosy patients with and without erythema nodosum leprosum signifying innate immune system activity

Lack of IκBNS promotes cholate-containing high-fat diet-induced inflammation and atherogenesis in low-density lipoprotein (LDL) receptor-deficient mice

BackgroundIκBNS, a nuclear IκB protein, regulates a subset of Toll-like receptor (TLR) dependent genes. A cholate-containing high-fat diet (HFD(CA(+))) induces TLR4 mediated early inflammatory response. The present study aims to clarify that the lack of IκBNS promotes atherogenesis in low-density lipoprotein receptor-deficient (LDLr−/−) mice fed HFD(CA(+)) compared with those fed a cholate-free HFD (HFD(CA(−))). Methods and resultsMice that lacked IκBNS (IκBNS−/−) were crossed with LDLr−/− mice and formation of atherosclerotic lesions was analyzed after 6-week consumption of HFD(CA(+)) or HFD(CA(−)). IκBNS−/−/LDLr−/− mice fed HFD(CA(+)) (IκBNS−/−/LDLr−/−(CA(+))) showed a 3.5-fold increase of atherosclerotic lesion size in the aorta compared with LDLr−/−(CA(+)) mice (p < 0.01), whereas there was no difference between LDLr−/−(CA(−)) and IκBNS−/−/LDLr−/−(CA(−)) mice. Immunohistochemical analysis of the aortic root revealed that HFD(CA(+)) significantly increased Mac-3 (macrophage)-positive area by 1.5-fold (p < 0.01) and TLR4, interleukin-6 (IL-6) expression by 1.7-fold (p < 0.05) and 1.5-fold (p < 0.05), respectively, in IκBNS−/−/LDLr−/−(CA(+)) compared with LDLr-/-−−(CA(+)) mice. Furthermore, active STAT3 (pSTAT3)-positive cells were significantly increased by 1.7-fold in the lesions of IκBNS−/−/LDLr−/−(CA(+)) compared with LDLr−/−(CA(+)) mice (p < 0.01). These findings suggest that IκBNS deficiency and HFD(CA(+)) promote atherogenesis in LDLr−/− mice via TLR4/IL-6/STAT3 pathway. Finally, we showed that the monocytes from peripheral blood of IκBNS−/−/LDLr−/−(CA(+)) mice were found to contain the highest proportion of Ly6Chi monocytes among the four groups, suggesting that lack of IκBNS enhanced inflammation in response to HFD(CA(+)) feeding. ConclusionsThe present study is the first to demonstrate that the activation of innate immune system using HFD(CA(+)) induced significant inflammation and atherogenesis in IκBNS−/−/LDLr−/− compared with LDLr−/− mice.

Lithium: Immunomodulatory and Anti-Infectious Activities

Lithium (Li), a well-known immunomodulatory agent, has been in use for the treatment of several infectious diseases. Li mainly acts through GSK3β inactivation and several other signalling pathways, which are directly involved in the activation of innate immune system. Li therapy has been shown to cause effective modulation of various inflammatory cytokines, and has also been shown to boost immunity in several disease models. Apart from treatment for mania, Li has also been proved to be effective against infections caused by viruses, bacteria, parasites, and certain life-style disorders. Its effects, ranging from common defensive capabilities to complex pathways for protection of human body, make Li extraordinary. Thus, Li is an absolute requirement that can be a solution for some of the immune related disorders. This review mainly focuses on pharmacology, immune reactions of different cell types, and anti-infectious activities of Li.

Toll-like receptor 7 deficiency promotes survival and reduces adverse left ventricular remodelling after myocardial infarction.

The Toll-like receptor 7 (TLR7) is an intracellular innate immune receptor activated by nucleic acids shed from dying cells leading to activation of the innate immune system. Since innate immune system activation is involved in the response to myocardial infarction (MI), this study aims to identify if TLR7 is involved in post-MI ischaemic injury and adverse remodelling after MI. TLR7 involvement in MI was investigated in human tissue from patients with ischaemic heart failure, as well as in a mouse model of permanent left anterior descending artery occlusion in C57BL/6J wild type and TLR7 deficient (TLR7-/-) mice. TLR7 expression was up-regulated in human and mouse ischaemic myocardium after MI. Compared to wild type mice, TLR7-/- mice had less acute cardiac rupture associated with blunted activation of matrix metalloproteinase 2, increased expression of tissue inhibitor of metalloproteinase 1, recruitment of more myofibroblasts, and the formation of a myocardial scar with higher collagen fibre density. Furthermore, inflammatory cell influx and inflammatory cytokine expression post-MI were reduced in the TLR7-/- heart. During a 28-day follow-up after MI, TLR7 deficiency resulted in less chronic adverse left ventricular remodelling and better cardiac function. Bone marrow (BM) transplantation experiments showed that TLR7 deficiency in BM-derived cells preserved cardiac function after MI. In acute MI, TLR7 mediates the response to acute cardiac injury and chronic remodelling probably via modulation of post-MI scar formation and BM-derived inflammatory infiltration of the myocardium.

Role of brown adipose tissue in modulating adipose tissue inflammation and insulin resistance in high-fat diet fed mice

Obesity results in the chronic activation of innate immune system and subsequently sets in diabetes. Aim of the study was to investigate the immunometabolic role of brown adipose tissue (BAT) in the obesity. We performed both BAT transplantation as well as extirpation experiments in the mouse model of high-fat diet (HFD)-induced obesity. We carried out immune cell profiling in the stromal vascular fraction (SVF) isolated from epididymal white adipose tissue (eWAT). BAT transplantation reversed HFD-induced increase in body weight gain and insulin resistance without altering diet intake. Importantly, BAT transplantation attenuated the obesity-associated adipose tissue inflammation in terms of decreased pro-inflammatory M1-macrophages, cytotoxic CD8a T-cells and restored anti-inflammatory regulatory T-cells (Tregs) in the eWAT. BAT transplantation also improved endogenous BAT activity by elevating protein expression of browning markers (UCP-1, PRDM16 and PGC1α) in it. In addition, BAT transplantation promoted the eWAT expression of various genes involved in fatty acid oxidation (such as Elvol3 and Tfam,). In contrast, extirpation of the interscapular BAT exacerbated HFD-induced obesity, insulin resistance and adipose tissue inflammation (by increasing M1 macrophages, CD8a T-cell and decreasing Tregs in eWAT). Taken together, our results suggested an important role of BAT in combating obesity-associated metabolic complications. These results open a novel therapeutic option to target obesity and related metabolic disorders like type 2 diabetes.

Gut Microbiota Dysbiosis and Their Impact on Biochemical and Inflammatory Profiles in Cafeteria Diet Fed Sprague Dawley Rats

Gut microbiota plays a major role in regulating the host metabolism and immune system. However, the structure of microbiome population is altered constantly by diverse factors including diet and environment. In particular, the gut microbiome dynamics is influenced by diet composition and their associated metabolites. Many studies in the recent past reported on diet induced dysbiosis in the gut microbiome, the modulating ratio between Firmicutes and Bacteroidetes plays a central role in maintaining the microbiome diversity in the gut and their abundance regulates obese conditions. Although there are several reports on gut microbial dysbiosis (Firmicutes/Bacteroidetes) at phylum level but only few of them highlight at the genera level. In the present study, we focused more on the impact of cafeteria diet (CAF) with respect to the gut microbiome richness at the genera level in SD rats. Three weeks old Sprague Dawley (SD) rats were fed with normal chow diet and cafeteria diet (CAF). After 10 weeks, serum, tissue samples (small intestine and cecum), cecum fecal and fecal pellet were collected. Biochemical analysis from serum, Gene expression analysis of pro-inflammatory markers from tissues and microbiome analysis from fecal samples were analysed. CAF diet fed rat in the present study developed obesity with increased body weight, few of them developed the resistance to weight gain (WGR) and these animal shows significantly increased abundance of Bacteriodetes-Prevotella compared to obese animals. This study suggests that detailed research needed to address the contribution of microbiota abundance at the genera level. We further explored the influence of diet induced microbiota changes on immune response; increase in Bacteroidetes leads to increased LPS and this in turn elicit immune reaction in the gut. Moreover, variation in gut microbiota also affects the gut barrier function (Tight junction proteins) and increase metabolic endotoxemia that leads to activation of innate immune system and low-grade inflammation. Further studies on these lines targeting the microbiota changes in the gut at the genera level is warranted to gain more knowledge.

Osteoclasts in the Inflammatory Arthritis: Implications for Pathologic Osteolysis.

The enhanced differentiation and activation of osteoclasts (OCs) in the inflammatory arthritis such as rheumatoid arthritis (RA) and gout causes not only local bone erosion, but also systemic osteoporosis, leading to functional disabilities and morbidity. The induction and amplification of NFATc1, a master regulator of OC differentiation, is mainly regulated by receptor activator of NF-κB (RANK) ligand-RANK and calcium signaling which are amplified in the inflammatory milieu, as well as by inflammatory cytokines such as TNFα, IL-1β and IL-6. Moreover, the predominance of CD4+ T cell subsets, which varies depending on the condition of inflammatory diseases, can determine the fate of OC differentiation. Anti-citrullinated peptide antibodies which are critical in the pathogenesis of RA can bind to the citrullinated vimentin on the surface of OC precursors, and in turn promote OC differentiation and function via IL-8. In addition to adaptive immunity, the activation of innate immune system including the nucleotide oligomerization domain leucine rich repeat with a pyrin domain 3 inflammasome and TLRs can regulate OC maturation. The emerging perspectives about the diverse and close interactions between the immune cells and OCs in inflammatory milieu can have a significant impact on the future direction of drug development.