scholarly journals Kallistatin Modulates Immune Cells and Confers Anti-Inflammatory Response To Protect Mice from Group A Streptococcal Infection

2013 ◽  
Vol 57 (11) ◽  
pp. 5366-5372 ◽  
Author(s):  
Shiou-Ling Lu ◽  
Chiau-Yuang Tsai ◽  
Yueh-Hsia Luo ◽  
Chih-Feng Kuo ◽  
Wei-Chieh Lin ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Streptococcal Toxic Shock Syndrome ◽  
Local Infection ◽  
Skin Damage ◽  
Bacterial Killing ◽  
Local Skin ◽  
Group A ◽  
Anti Inflammatory

ABSTRACTGroup A streptococcus (GAS) infection may cause severe life-threatening diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome. Despite the availability of effective antimicrobial agents, there has been a worldwide increase in the incidence of invasive GAS infection. Kallistatin (KS), originally found to be a tissue kallikrein-binding protein, has recently been shown to possess anti-inflammatory properties. However, its efficacy in microbial infection has not been explored. In this study, we transiently expressed the human KS gene by hydrodynamic injection and investigated its anti-inflammatory and protective effects in mice via air pouch inoculation of GAS. The results showed that KS significantly increased the survival rate of GAS-infected mice. KS treatment reduced local skin damage and bacterial counts compared with those in mice infected with GAS and treated with a control plasmid or saline. While there was a decrease in immune cell infiltration of the local infection site, cell viability and antimicrobial factors such as reactive oxygen species actually increased after KS treatment. The efficiency of intracellular bacterial killing in neutrophils was directly enhanced by KS administration. Several inflammatory cytokines, including tumor necrosis factor alpha, interleukin 1β, and interleukin 6, in local infection sites were reduced by KS. In addition, KS treatment reduced vessel leakage, bacteremia, and liver damage after local infection. Therefore, our study demonstrates that KS provides protection in GAS-infected mice by enhancing bacterial clearance, as well as reducing inflammatory responses and organ damage.

scholarly journals Dextromethorphan Efficiently Increases Bactericidal Activity, Attenuates Inflammatory Responses, and Prevents Group A Streptococcal Sepsis

2011 ◽  
Vol 55 (3) ◽  
pp. 967-973 ◽  
Author(s):  
Ming-Han Li ◽  
Yueh-Hsia Luo ◽  
Chiou-Feng Lin ◽  
Yu-Tzu Chang ◽  
Shiou-Ling Lu ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Inflammatory Responses ◽  
Group A Streptococcus ◽  
Wide Spectrum ◽  
Serum Levels ◽  
Streptococcal Toxic Shock Syndrome ◽  
Necrosis Factor Alpha ◽  
Bacterial Killing ◽  
Air Pouch ◽  
Group A

ABSTRACTGroup A streptococcus (GAS) is an important human pathogen that causes a wide spectrum of diseases, ranging from mild throat and skin infections to severe invasive diseases such as necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM), a dextrorotatory morphinan and a widely used antitussive drug, has recently been reported to possess anti-inflammatory properties. In this study, we investigated the potential protective effect of DM in GAS infection using an air pouch infection mouse model. Our results showed that DM treatment increased the survival rate of GAS-infected mice. Bacterial numbers in the air pouch were lower in mice treated with DM than in those infected with GAS alone. The bacterial elimination efficacy was associated with increased cell viability and bactericidal activity of air-pouch-infiltrating cells. Moreover, DM treatment prevented bacterial dissemination in the blood and reduced serum levels of the proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and IL-1β and the chemokines monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 2 (MIP-2), and RANTES. In addition, GAS-induced mouse liver injury was reduced by DM treatment. Taken together, DM can increase bacterial killing and reduce inflammatory responses to prevent sepsis in GAS infection. The consideration of DM as an adjunct treatment in combination with antibiotics against bacterial infection warrants further study.

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.

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 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 Efferocytosis potentiates the expression of arachidonate 15-lipoxygenase (ALOX15) in alternatively activated human macrophages through LXR activation

2020 ◽  
Author(s):  
Ryan G. Snodgrass ◽  
Yvonne Benatzy ◽  
Tobias Schmid ◽  
Dmitry Namgaladze ◽  
Malwina Mainka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tissue Repair ◽  
Cell Function ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Th2 Cytokines ◽  
Alternatively Activated Macrophages ◽  
Anti Inflammatory ◽  
Alternatively Activated

Abstract Macrophages acquire anti-inflammatory and proresolving functions to facilitate resolution of inflammation and promote tissue repair. While alternatively activated macrophages (AAMs), also referred to as M2 macrophages, polarized by type 2 (Th2) cytokines IL-4 or IL-13 contribute to the suppression of inflammatory responses and play a pivotal role in wound healing, contemporaneous exposure to apoptotic cells (ACs) potentiates the expression of anti-inflammatory and tissue repair genes. Given that liver X receptors (LXRs), which coordinate sterol metabolism and immune cell function, play an essential role in the clearance of ACs, we investigated whether LXR activation following engulfment of ACs selectively potentiates the expression of Th2 cytokine-dependent genes in primary human AAMs. We show that AC uptake simultaneously upregulates LXR-dependent, but suppresses SREBP-2-dependent gene expression in macrophages, which are both prevented by inhibiting Niemann–Pick C1 (NPC1)-mediated sterol transport from lysosomes. Concurrently, macrophages accumulate sterol biosynthetic intermediates desmosterol, lathosterol, lanosterol, and dihydrolanosterol but not cholesterol-derived oxysterols. Using global transcriptome analysis, we identify anti-inflammatory and proresolving genes including interleukin-1 receptor antagonist (IL1RN) and arachidonate 15-lipoxygenase (ALOX15) whose expression are selectively potentiated in macrophages upon concomitant exposure to ACs or LXR agonist T0901317 (T09) and Th2 cytokines. We show priming macrophages via LXR activation enhances the cellular capacity to synthesize inflammation-suppressing specialized proresolving mediator (SPM) precursors 15-HETE and 17-HDHA as well as resolvin D5. Silencing LXRα and LXRβ in macrophages attenuates the potentiation of ALOX15 expression by concomitant stimulation of ACs or T09 and IL-13. Collectively, we identify a previously unrecognized mechanism of regulation whereby LXR integrates AC uptake to selectively shape Th2-dependent gene expression in AAMs.

scholarly journals Anti-Inflammatory and Immunosuppressive Effects of the A2AAdenosine Receptor

2011 ◽  
Vol 11 ◽  
pp. 320-339 ◽  
Author(s):  
Gillian R. Milne ◽  
Timothy M. Palmer
Keyword(s):  
Molecular Mechanisms ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Current Evidence ◽  
Receptor Subtypes ◽  
Protective Effects ◽  
Stress Injury ◽  
Anti Inflammatory

The production of adenosine represents a critical endogenous mechanism for regulating immune and inflammatory responses during conditions of stress, injury, or infection. Adenosine exerts predominantly protective effects through activation of four 7-transmembrane receptor subtypes termed A1, A2A, A2B, and A3, of which the A2Aadenosine receptor (A2AAR) is recognised as a major mediator of anti-inflammatory responses. The A2AAR is widely expressed on cells of the immune system and numerousin vitrostudies have identified its role in suppressing key stages of the inflammatory process, including leukocyte recruitment, phagocytosis, cytokine production, and immune cell proliferation. The majority of actions produced by A2AAR activation appear to be mediated by cAMP, but downstream events have not yet been well characterised. In this article, we review the current evidence for the anti-inflammatory effects of the A2AAR in different cell types and discuss possible molecular mechanisms mediating these effects, including the potential for generalised suppression of inflammatory gene expression through inhibition of the NF-κB and JAK/STAT proinflammatory signalling pathways. We also evaluate findings fromin vivostudies investigating the role of the A2AAR in different tissues in animal models of inflammatory disease and briefly discuss the potential for development of selective A2AAR agonists for use in the clinic to treat specific inflammatory conditions.

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 Diflunisal targets the HMGB1/CXCL12 heterocomplex and blocks immune cell recruitment

2019 ◽  
Author(s):  
Federica De Leo ◽  
Giacomo Quilici ◽  
Mario Tirone ◽  
Valeria Mannella ◽  
Francesco De Marchis ◽  
...  
Keyword(s):  
Rational Design ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Inflammatory Cells ◽  
Cell Recruitment ◽  
Redox States ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

AbstractExtracellular HMGB1 triggers inflammation following infection or injury, and supports tumorigenesis in inflammation-related malignancies. HMGB1 has several redox states: reduced HMGB1 recruits inflammatory cells to injured tissues forming a heterocomplex with CXCL12 and signaling via its receptor CXCR4; disulfide-containing HMGB1 binds to TLR4 and promotes inflammatory responses. Here we show that Diflunisal, an aspirin-like nonsteroidal anti-inflammatory drug (NSAID) that has been in clinical use for decades, specifically inhibits in vitro and in vivo the chemotactic activity of HMGB1 at nanomolar concentrations, at least in part by binding directly to both HMGB1 and CXCL12 and disrupting their heterocomplex. Importantly, Diflunisal does not inhibit TLR4-dependent responses. Our findings clarify the mode of action of Diflunisal, and open the way to the rational design of functionally specific anti-inflammatory drugs.

scholarly journals Evaluation of Berberine as an Adjunct to TB Treatment

2021 ◽  
Vol 12 ◽  
Author(s):  
Mumin Ozturk ◽  
Julius E. Chia ◽  
Rudranil Hazra ◽  
Mohd Saqib ◽  
Rebeng A. Maine ◽  
...  
Keyword(s):  
Immune Cell ◽  
Inflammatory Responses ◽  
Late Onset ◽  
Communicable Disease ◽  
Synergistic Effects ◽  
Disease Stage ◽  
Adjunctive Treatment ◽  
Lung Pathology ◽  
Bacterial Killing ◽  
Inflammatory Status

Tuberculosis (TB) is the global health problem with the second highest number of deaths from a communicable disease after COVID-19. Although TB is curable, poor health infrastructure, long and grueling TB treatments have led to the spread of TB pandemic with alarmingly increasing multidrug-resistant (MDR)-TB prevalence. Alternative host modulating therapies can be employed to improve TB drug efficacies or dampen the exaggerated inflammatory responses to improve lung function. Here, we investigated the adjunct therapy of natural immune-modulatory compound berberine in C57BL/6 mouse model of pulmonary TB. Berberine treatment did not affect Mtb growth in axenic cultures; however, it showed increased bacterial killing in primary murine bone marrow-derived macrophages and human monocyte-derived macrophages. Ad libitum berberine administration was beneficial to the host in combination with rifampicin and isoniazid. Berberine adjunctive treatment resulted in decreased lung pathology with no additive or synergistic effects on bacterial burdens in mice. Lung immune cell flow cytometry analysis showed that adjunctive berberine treatment decreased neutrophil, CD11b+ dendritic cell and recruited interstitial macrophage numbers. Late onset of adjunctive berberine treatment resulted in a similar phenotype with consistently reduced numbers of neutrophils both in lungs and the spleen. Together, our results suggest that berberine can be supplemented as an immunomodulatory agent depending on the disease stage and inflammatory status of the host.

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