scholarly journals Modulation of monocyte responses by progressive multiple sclerosis therapy.

2021 ◽  
Author(s):  
◽  
Carl Beyers
Keyword(s):  
Multiple Sclerosis ◽  
Inflammatory Cytokines ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Neurodegenerative Disorder ◽  
Cell Activity ◽  
Cell Subset ◽  
Disease Heterogeneity ◽  
Receptor Affinity ◽  
Anti Inflammatory

<p>Multiple sclerosis (MS) is an immune-mediated neurodegenerative disorder that is distinguished by neuroinflammation and demyelination. MS is severely debilitating and remains the most common cause of disability arising from non-traumatic brain and CNS damage in adults. In its progressive phase there are no effective treatments, so new therapy options are an urgent research priority. Extensive work has been done on the role of the adaptive immune system in contributing to the disease pathology and on the effects of therapies targeting lymphocytes in relapsing-remitting MS. Fewer studies have examined innate immune cells in people with progressive MS. This thesis addresses that gap by profiling monocyte phenotype and function in response to new and repurposed drugs that may provide benefit in progressive MS. This was achieved by modelling the drugs’ effects in vitro using peripheral blood cells from people with progressive MS and healthy subjects.   Clozapine is an atypical antipsychotic with broad receptor affinity that is primarily used to treat refractory schizophrenia. In addition to is antipsychotic action through dopamine receptor (DR) D2, its broad neuro-immune receptor affinity is thought to dampen inflammatory responses in the CNS. This thesis highlights clozapine’s anti-inflammatory effect by demonstrating a reduction in the expression of pro-inflammatory cytokines that are associated with MS pathology in treated monocytes. Clozapine also induced a significant increase in the expression of D1. We observed that D1 expression changes happened alongside alterations to immune cell activity and that MS participant monocytes were much more susceptible to DR expression changes compared to healthy people. Together this data substantiates clozapine as a potential treatment for progressive disease.   MIS416 is a large, non-soluble microparticle suspension that induces nuclear factor kappa B (NFB) dependent cytokine induction. We show here that monocytes are key cytokine responder cells to MIS416 and explore the molecular mechanism by demonstrating its effects on transcription factor activity. Our data showing increased production of cytokines by MIS416 suggests a route of treatment efficacy through tolerisation mechanisms, and by reducing inflammation through upregulation of anti-inflammatory cytokines and negative feedback from pro-inflammatory cytokine release. Furthermore, we demonstrate how disease heterogeneity, phenotype, and genotype could significantly affect drug response outcomes in patients who received the drug as part of a phase 2 clinical trial.   Much of this work was done using new spectral cytometer technology. Its use allowed for the novel approach that enabled the subtraction of autofluorescent noise from out data, and we demonstrate its efficient functioning, ease of use, and utility in acquiring high dimensional datasets. The resulting large dataset allowed us the opportunity to interrogate it using bioinformatics tools, and we show their utility as adjunct tools to conventional methods of gating and statistical analysis. These analyses help demonstrate that monocytes are a heterogenous immune cell subset that is functionally distinct in people with progressive MS when compared to monocytes from healthy individuals.</p>

scholarly journals Modulation of monocyte responses by progressive multiple sclerosis therapy.

2021 ◽  
Author(s):  
◽  
Carl Beyers
Keyword(s):  
Multiple Sclerosis ◽  
Inflammatory Cytokines ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Neurodegenerative Disorder ◽  
Cell Activity ◽  
Cell Subset ◽  
Disease Heterogeneity ◽  
Receptor Affinity ◽  
Anti Inflammatory

<p>Multiple sclerosis (MS) is an immune-mediated neurodegenerative disorder that is distinguished by neuroinflammation and demyelination. MS is severely debilitating and remains the most common cause of disability arising from non-traumatic brain and CNS damage in adults. In its progressive phase there are no effective treatments, so new therapy options are an urgent research priority. Extensive work has been done on the role of the adaptive immune system in contributing to the disease pathology and on the effects of therapies targeting lymphocytes in relapsing-remitting MS. Fewer studies have examined innate immune cells in people with progressive MS. This thesis addresses that gap by profiling monocyte phenotype and function in response to new and repurposed drugs that may provide benefit in progressive MS. This was achieved by modelling the drugs’ effects in vitro using peripheral blood cells from people with progressive MS and healthy subjects.   Clozapine is an atypical antipsychotic with broad receptor affinity that is primarily used to treat refractory schizophrenia. In addition to is antipsychotic action through dopamine receptor (DR) D2, its broad neuro-immune receptor affinity is thought to dampen inflammatory responses in the CNS. This thesis highlights clozapine’s anti-inflammatory effect by demonstrating a reduction in the expression of pro-inflammatory cytokines that are associated with MS pathology in treated monocytes. Clozapine also induced a significant increase in the expression of D1. We observed that D1 expression changes happened alongside alterations to immune cell activity and that MS participant monocytes were much more susceptible to DR expression changes compared to healthy people. Together this data substantiates clozapine as a potential treatment for progressive disease.   MIS416 is a large, non-soluble microparticle suspension that induces nuclear factor kappa B (NFB) dependent cytokine induction. We show here that monocytes are key cytokine responder cells to MIS416 and explore the molecular mechanism by demonstrating its effects on transcription factor activity. Our data showing increased production of cytokines by MIS416 suggests a route of treatment efficacy through tolerisation mechanisms, and by reducing inflammation through upregulation of anti-inflammatory cytokines and negative feedback from pro-inflammatory cytokine release. Furthermore, we demonstrate how disease heterogeneity, phenotype, and genotype could significantly affect drug response outcomes in patients who received the drug as part of a phase 2 clinical trial.   Much of this work was done using new spectral cytometer technology. Its use allowed for the novel approach that enabled the subtraction of autofluorescent noise from out data, and we demonstrate its efficient functioning, ease of use, and utility in acquiring high dimensional datasets. The resulting large dataset allowed us the opportunity to interrogate it using bioinformatics tools, and we show their utility as adjunct tools to conventional methods of gating and statistical analysis. These analyses help demonstrate that monocytes are a heterogenous immune cell subset that is functionally distinct in people with progressive MS when compared to monocytes from healthy individuals.</p>

Anti-Inflammatory Agents: An Approach to Prevent Cognitive Decline in Alzheimer’s Disease

2021 ◽  
pp. 1-16
Author(s):  
Staley A. Brod
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trial ◽  
Cognitive Decline ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Type I ◽  
Type I Ifn ◽  
Anti Inflammatory

Systemic inflammation is an organism’s response to an assault by the non-self. However, that inflammation may predispose humans to illnesses targeted to organs, including Alzheimer’s disease (AD). Lesions in AD have pro-inflammatory cytokines and activated microglial/monocyte/macrophage cells. Up to this point, clinical trials using anti-amyloid monoclonal antibodies have not shown success. Maybe it is time to look elsewhere by combating inflammation. Neuroinflammation with CNS cellular activation and excessive expression of immune cytokines is suspected as the “principal culprit” in the higher risk for sporadic AD. Microglia, the resident immune cell of the CNS, perivascular myeloid cells, and activated macrophages produce IL-1, IL-6 at higher levels in patients with AD. Anti-inflammatory measures that target cellular/cytokine-mediated damage provide a rational therapeutic strategy. We propose a clinical trial using oral type 1 IFNs to act as such an agent; one that decreases IL-1 and IL-6 secretion by activating lamina propria lymphocytes in the gut associated lymphoid tissue with subsequent migration to the brain undergoing inflammatory responses. A clinical trial would be double-blind, parallel 1-year clinical trial randomized 1 : 1 oral active type 1 IFN versus best medical therapy to determine whether ingested type I IFN would decrease the rate of cognitive decline in mild cognitive impairment or mild AD. Using cognitive psychometrics, imaging, and fluid biomarkers (MxA for effective type I IFN activity beyond the gut), we can determine if oral type I IFN can prevent cognitive decline in AD.

scholarly journals Squalene Stimulates a Key Innate Immune Cell to Foster Wound Healing and Tissue Repair

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Cristina Sánchez-Quesada ◽  
Alicia López-Biedma ◽  
Estefania Toledo ◽  
José J. Gaforio
Keyword(s):  
Wound Healing ◽  
Inflammatory Cytokines ◽  
Tissue Repair ◽  
Immune Cell ◽  
Critical Role ◽  
Virgin Olive Oil ◽  
Skin Damage ◽  
Macrophage Response ◽  
Anti Inflammatory ◽  
Minor Compounds

Anti-inflammatory effects of virgin olive oil (VOO) have been described recently, along with its wound healing effect. One of the main minor compounds found in VOO is squalene (SQ), which also possesses preventive effects against skin damage and anti-inflammatory properties. The inflammatory response is involved in wound healing and manages the whole process by macrophages, among others, as the main innate cells with a critical role in the promotion and resolution of inflammation for tissue repair. Because of that, this work is claimed to describe the role that squalene exerts in the immunomodulation of M1 proinflammatory macrophages, which are the first cells implicate in recent injuries. Pro- and anti-inflammatory cytokines were analysed using TPH1 cell experimental model. SQ induced an increase in the synthesis of anti-inflammatory cytokines, such as IL-10, IL-13, and IL-4, and a decrease in proinflammatory signals, such as TNF-α and NF-κB in M1 proinflammatory macrophages. Furthermore, SQ enhanced remodelling and repairing signals (TIMP-2) and recruitment signals of eosinophils and neutrophils, responsible for phagocytosis processes. These results suggest that SQ is able to promote wound healing by driving macrophage response in inflammation. Therefore, squalene could be useful at the resolution stage of wound healing.

Abstract 553: Siglec-1 (CD169) on Monocytes/Macrophages: A New Receptor For Extracellular Self-RNA in Triggering Inflammatory Responses via the Sheddase TACE/ADAM17

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Hector A Cabrera-Fuentes ◽  
Klaus T Preissner ◽  
William A Boisvert
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Transmembrane Protein ◽  
Macrophage Polarization ◽  
Extracellular Rna ◽  
Tnf Α ◽  
M1 Phenotype ◽  
Phenotype Markers ◽  
Anti Inflammatory

As an important component of atherosclerosis, monocytes/macrophages respond to external stimuli with rapid changes in their expression of many inflammation-related genes to undergo polarization towards the M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotype. Although sialoadhesin (Sn), also known as SIGLEC-1 or CD169, is a transmembrane protein receptor expressed on monocytes and macrophages whether it has a role in macrophage polarization and ultimately, macrophage-driven atherogenesis, has not been investigated. We have previously shown that, independently of Toll-like receptor signaling, extracellular RNA (eRNA) could exert pro-thrombotic and pro-inflammatory properties in the cardiovascular system by inducing cytokine mobilization. In the current study, recombinant mouse macrophage CSF[[Unable to Display Character: &#8211;]]driven bone marrow-derived macrophage (BMDM) differentiation was found to be skewed towards the M1 phenotype by exposure of cells to eRNA. This resulted in up-regulation of inflammatory markers, whereas anti-inflammatory genes were significantly down-regulated by eRNA. Interestingly, eRNA was released from BMDM under hypoxia and induced TNF-α liberation by activating TNF-α converting enzyme (TACE) to provoke inflammation. Conversely, TNF-α promoted eRNA release, especially under hypoxia, feeding a vicious cycle of cell damage. Administration of RNase1 or TAPI (a TACE-inhibitor) prevented the production of inflammatory mediators. Murine BMDM isolated from mice deficient in sialoadhesin had the opposite reaction to eRNA treatment with a prominent down-regulation of pro-inflammatory cytokines/M1 phenotype markers, while anti-inflammatory cytokines/M2 phenotype markers were significantly raised. In keeping with the proposed role of eRNA as a pro-inflammatory “alarm signal”, these data further shed light on the role of eRNA in macrophage function in the context of chronic inflammatory diseases such as atherosclerosis. The identification of sialoadhesin as putative eRNA recognition site on macrophages may allow further investigation of the underlying mechanisms of eRNA-macrophage interaction and related signal transduction pathways. Siglec-1 thereby may provides a new target to treat eRNA-mediated vascular diseases.

scholarly journals Antioxidative, Antiapoptotic, and Anti-Inflammatory Effects of Apamin in a Murine Model of Lipopolysaccharide-Induced Acute Kidney Injury

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5717 ◽  
Author(s):  
Jung-Yeon Kim ◽  
Jaechan Leem ◽  
Kwan-Kyu Park
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Therapeutic Option ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Kidney Injury ◽  
Heme Oxygenase 1 ◽  
Anti Inflammatory

Sepsis is the major cause of acute kidney injury (AKI) in severely ill patients, but only limited therapeutic options are available. During sepsis, lipopolysaccharide (LPS), an endotoxin derived from bacteria, activates signaling cascades involved in inflammatory responses and tissue injury. Apamin is a component of bee venom and has been shown to exert antioxidative, antiapoptotic, and anti-inflammatory activities. However, the effect of apamin on LPS-induced AKI has not been elucidated. Here, we show that apamin treatment significantly ameliorated renal dysfunction and histological injury, especially tubular injury, in LPS-injected mice. Apamin also suppressed LPS-induced oxidative stress through modulating the expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and heme oxygenase-1. Moreover, tubular cell apoptosis with caspase-3 activation in LPS-injected mice was significantly attenuated by apamin. Apamin also inhibited cytokine production and immune cell accumulation, suppressed toll-like receptor 4 pathway, and downregulated vascular adhesion molecules. Taken together, these results suggest that apamin ameliorates LPS-induced renal injury through inhibiting oxidative stress, apoptosis of tubular epithelial cells, and inflammation. Apamin might be a potential therapeutic option for septic AKI.

scholarly journals 13 Lipocalin 2 exerts protective activity by alleviating inflammatory responses

2019 ◽  
Vol 97 (Supplement_3) ◽  
pp. 17-19
Author(s):  
Shuhui Li
Keyword(s):  
Inflammatory Cytokines ◽  
Protective Factor ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Enzyme Linked Immunosorbent Assay ◽  
Lipocalin 2 ◽  
Continuous Increase ◽  
Raw264.7 Macrophages ◽  
Arginase 1 ◽  
Anti Inflammatory

Abstract Lipocalin 2 (Lcn2) is an essential component of the innate immune system and exerts significant immunomodulatory effects in vitro. The aim of current study was to investigate the expression profile of Lcn2 during inflammatory process and explore the role of Lcn2 in the anti-inflammatory responses. Western blot, real-time quantitative PCR, immunofluorescence (IF) and enzyme-linked immunosorbent assay (ELISA) were employed. Firstly, we evaluated the temporospatial expression of Lcn2 of mice after inflammatory stimuli by lipopolysaccharides (LPS). In vivo, LPS induced both mRNA and protein levels of Lcn2 significantly (P &lt; 0.01) in liver, jejunum and ileum. Lcn2 exhibited a continuous increase by 8 h and peaked by 24 h post challenges. Secondly, we challenged Lcn2-deficient (Lcn2-/-) mice and wild-type (WT) mice with peripheral LPS and determined effects on inflammation. In contrast to WT mice, Lcn2-/- mice showed distinct inflammatory injury in liver, jejunum, ileum and spleen with significantly elevated pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-1b (IL-1b) and decreased anti-inflammatory cytokine interleukin-10 (IL-10). Thirdly, we isolated bone marrow-derived macrophages (BMDM) from Lcn2-/- mice and WT mice to evaluate their functions. After LPS challenge, Lcn2-/- BMDM showed aggravated inflammatory reaction as pro-inflammatory factors tumour necrosis factor-α (TNF-α), IL-6, IL-1b and inducible nitric oxide synthase (iNOS) increased (P &lt; 0.05) while anti-inflammatory cytokines IL-10, transforming growth factor β1 (TGF-β1) and arginase-1(Arg-1) decreased significantly (P &lt; 0.05) compared with WT BMDM. This phenomenon could be relieved when adding recombinant Lcn2 (P &lt; 0.05). The exogenous addition of Lcn2 on mice RAW264.7 macrophages stimulated by LPS also conformed this point. These findings demonstrated that Lcn2 served as a potent protective factor in response to systemic inflammation, and elevated Lcn2 expression during inflammatory conditions was presumed to play an effective role in alleviating inflammatory responses.

scholarly journals The FLUENT study design: investigating immune cell subset and neurofilament changes in patients with relapsing multiple sclerosis treated with fingolimod

2019 ◽  
Vol 5 (1) ◽  
pp. 205521731881924 ◽  
Author(s):  
Jeffrey A Cohen ◽  
Amit Bar-Or ◽  
Bruce A C Cree ◽  
Yang Mao-Draayer ◽  
May H Han ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune System ◽  
Immune Cell ◽  
Cell Subset ◽  
Adaptive Immune System ◽  
Study Cohort ◽  
Open Label ◽  
Receptor Modulator ◽  
Circulating Lymphocytes ◽  
B Cell Subsets

Background Fingolimod is a sphingosine 1-phosphate receptor modulator for the treatment of patients with relapsing forms of multiple sclerosis (RMS). Fingolimod sequesters lymphocytes within lymphoid tissue thereby reducing the counts of circulating lymphocytes. However, fingolimod’s effects on the innate and adaptive components of the immune system are incompletely understood. Objective The FLUENT study will investigate temporal changes in circulating immune cell subsets in patients with RMS treated with fingolimod. Secondary objectives include examining the association between anti-John Cunningham virus (JCV) antibody status/index and phenotypic changes in innate and T and B cell subsets in patients on fingolimod therapy, and the association between serum neurofilament levels and clinical outcomes. Methods FLUENT is a prospective, multicenter, two-cohort, nonrandomized, open-label Phase IV study. Cohort 1 will include fingolimod-naïve patients and Cohort 2 will include patients who have received fingolimod 0.5 mg/day continuously for ≥2 years. Changes in the cellular components of the innate and adaptive immune system will be characterized over 12 months. Results The study is ongoing. Conclusion FLUENT may provide evidence for the use of immunologic profiling in predicting efficacy and risk of infection in patients with RMS treated with fingolimod.

scholarly journals The Anti-Inflammatory Effects of Angiogenin in an Endotoxin Induced Uveitis in Rats

2020 ◽  
Vol 21 (2) ◽  
pp. 413
Author(s):  
Jihae Park ◽  
Jee Taek Kim ◽  
Soo Jin Lee ◽  
Jae Chan Kim
Keyword(s):  
Western Blot ◽  
Inflammatory Cytokines ◽  
Aqueous Humor ◽  
Rat Model ◽  
Inflammatory Responses ◽  
Inflammatory Cells ◽  
Ocular Tissue ◽  
Tnf Α ◽  
Anti Inflammatory

Angiogenin (ANG) is involved in the innate immune system and inflammatory disease. The aim of this study is to evaluate the anti-inflammatory effects of ANG in an endotoxin induced uveitis (EIU) rat model and the pathways involved. EIU rats were treated with balanced salt solution (BSS), a non-functional mutant ANG (mANG), or wild-type ANG (ANG). The integrity of the blood-aqueous barrier was evaluated by the infiltrating cell and protein concentrations in aqueous humor. Histopathology, Western blot, and real-time qRT-PCR of aqueous humor and ocular tissue were performed to analyze inflammatory cytokines and transcription factors. EIU treated with ANG had decreased inflammatory cells and protein concentrations in the anterior chamber. Compared to BSS and mANG, ANG treatment showed reduced expression of IL-1β, IL-8, TNF-α, and Myd88, while the expression of IL-4 and IL-10 was increased. Western blot of ANG treatment showed decreased expression of IL-6, inducible nitric oxide synthase (iNOS), IL-1β, TNF-α, and phosphorylated NF-κB and increased expression of IL-10. In conclusion, ANG seems to reduce effectively immune mediated inflammation in the EIU rat model by reducing the expression of proinflammatory cytokines, while increasing the expression of anti-inflammatory cytokines through pathways related to NF-κB. Therefore, ANG shows potential for effectively suppressing immune-inflammatory responses in vivo.

scholarly journals Growth differentiation factor-15 is associated with age-related monocyte immunosenescence

2020 ◽  
Author(s):  
Brandt D. Pence ◽  
Johnathan R. Yarbro ◽  
Russell S. Emmons
Keyword(s):  
Mitochondrial Function ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Cell Subset ◽  
Cytokine Gene Expression ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor ◽  
Age Related

ABSTRACTBackgroundImmunosenescence is an age-associated decrease in function of immune cells precipitated by a variety of mechanisms and affecting nearly every immune cell subset. In myeloid cell subsets, aging reduces numbers of phagocytes and impairs their functional abilities, including antigen presentation, phagocytosis, and bacterial clearance. Recently, we have described an aging effect on several functions indicating immunosenescence in monocytes, including impaired mitochondrial function and reduced inflammatory cytokine gene expression during stimulation with lipopolysaccharide (LPS). We hypothesized that circulating factors altered by the aging process underly these changes. Growth/differentiation factor-15 (GDF-15) is a distant member of the transforming growth factor-beta superfamily that has known anti-inflammatory effects in macrophages and has recently been shown to be highly differentially expressed during aging. We used biobanked serum and plasma samples to assay circulating GDF-15 levels in subjects from our previous studies and examined correlations between GDF-15 levels and monocyte mitochondrial function and inflammatory responses.ResultsMonocyte interleukin-6 production due to lipopolysaccharide stimulation was negatively correlated to plasma GDF-15 levels. Additionally, serum GDF-15 was positively correlated to circulating CD16+ monocyte proportions and negatively correlated to monocyte mitochondrial respiratory capacity.ConclusionsThe results of these analyses suggest that GDF-15 is a potential circulating factor affecting a variety of monocyte functions and promoting monocyte immunosenescence, and thus may be an attractive candidate for therapeutic intervention to ameliorate this.

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