scholarly journals FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages

2020 ◽  
Author(s):  
Dongxue Wang ◽  
Fei Liu ◽  
Liyun Zhu ◽  
Ping Lin ◽  
Fanyi Han ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Cell Sorting ◽  
Critical Role ◽  
Experimental Stroke ◽  
Fibroblast Growth Factor 21 ◽  
Ppar Γ ◽  
Promising Therapeutic Approach ◽  
Anti Inflammatory ◽  
Peripheral Immune Cells

Abstract Background: Resident microglia and macrophages are the predominant contributors to neuroinflammation and immune reactions, which play a critical role in the pathogenesis of ischemic brain injury. Controlling inflammatory responses is considered a promising therapeutic approach for stroke. Recombinant human fibroblast growth factor 21 (rhFGF21) has anti-inflammatory properties by modulating microglia and macrophages, but our knowledge of the inflammatory modulation of rhFGF21 in focal cerebral ischemia is lacking. Therefore, we investigated whether rhFGF21 improves ischemic outcomes in experimental stroke by targeting microglia and macrophages. Methods: C57BL/6 mice were subjected to transient middle cerebral artery occlusion (tMCAO) and randomly divided into groups that received intraperitoneal rhFGF21 or vehicle daily starting at 6 h after reperfusion. Behavior assessments were monitored for 14 d after tMACO and the gene expression levels of inflammatory cytokines were analyzed with qPCR. The phenotypic variation of microglia/macrophages and the presence of infiltrated immune cells were examined by flow cytometry and immunostaining. Additionally, magnetic cell sorting (MACS) in combination with fluorescence-activated cell sorting (FACS) was used to purify microglia and macrophages. Results: rhFGF21 administration ameliorated neurological deficits in behavioral tests by regulating the secretion of pro-inflammatory and anti-inflammatory cytokines. rhFGF21 also attenuated the polarization of microglia/macrophages toward the M1 phenotype and the accumulation of peripheral immune cells after stroke, accompanied by a temporal evolution of the phenotype of microglia/macrophages and infiltration of peripheral immune cells. Furthermore, rhFGF21 treatment through its actions on FGF receptor 1(FGFR1) inhibited M1 polarization of microglia and pro-inflammatory cytokine expression by suppressing nuclear factor-kappa B (NF-κB ) and upregulating peroxisome proliferator-activated receptor PPAR-γ. conclusion：In summary, rhFGF21 treatment promoted functional recovery in experimental stroke by modulating microglia/macrophage-mediated neuroinflammation via the NF-κB and PPAR-γ signaling pathways, making it a potential anti-inflammatory agent for stroke treatment. Keywords : rhFGF21, stroke, neuroinflammation, microglia/macrophage, NF-κB, PPAR-γ

scholarly journals FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages

2020 ◽  
Author(s):  
Dongxue Wang ◽  
Fei Liu ◽  
Liyun Zhu ◽  
Ping Lin ◽  
Fanyi Han ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Cell Sorting ◽  
Critical Role ◽  
Experimental Stroke ◽  
Fibroblast Growth Factor 21 ◽  
Ppar Γ ◽  
Promising Therapeutic Approach ◽  
Anti Inflammatory ◽  
Peripheral Immune Cells

Abstract Background: Resident microglia and macrophages are the predominant contributors to neuroinflammation and immune reactions, which play a critical role in the pathogenesis of ischemic brain injury. Controlling inflammatory responses is considered a promising therapeutic approach for stroke. Recombinant human fibroblast growth factor 21 (rhFGF21) has anti-inflammatory properties by modulating microglia and macrophages, but our knowledge of the inflammatory modulation of rhFGF21 in focal cerebral ischemia is lacking. Therefore, we investigated whether rhFGF21 improves ischemic outcomes in experimental stroke by targeting microglia and macrophages. Methods: C57BL/6 mice were subjected to transient middle cerebral artery occlusion (tMCAO) and randomly divided into groups that received intraperitoneal rhFGF21 or vehicle daily starting at 6 h after reperfusion. Behavior assessments were monitored for 14 d after tMACO and the gene expression levels of inflammatory cytokines were analyzed with qPCR. The phenotypic variation of microglia/macrophages and the presence of infiltrated immune cells were examined by flow cytometry and immunostaining. Additionally, magnetic cell sorting (MACS) in combination with fluorescence-activated cell sorting (FACS) was used to purify microglia and macrophages. Results: rhFGF21 administration ameliorated neurological deficits in behavioral tests by regulating the secretion of pro-inflammatory and anti-inflammatory cytokines. rhFGF21 also attenuated the polarization of microglia/macrophages toward the M1 phenotype and the accumulation of peripheral immune cells after stroke, accompanied by a temporal evolution of the phenotype of microglia/macrophages and infiltration of peripheral immune cells. Furthermore, rhFGF21 treatment through its actions on FGF receptor 1(FGFR1) inhibited M1 polarization of microglia and pro-inflammatory cytokine expression by suppressing nuclear factor-kappa B (NF-κB ) and upregulating peroxisome proliferator-activated receptor PPAR-γ. conclusion： In summary, rhFGF21 treatment promoted functional recovery in experimental stroke by modulating microglia/macrophage-mediated neuroinflammation via the NF-κB and PPAR-γ signaling pathways, making it a potential anti-inflammatory agent for stroke treatment.

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 Benznidazole Anti-Inflammatory Effects in Murine Cardiomyocytes and Macrophages Are Mediated by Class I PI3Kδ

2021 ◽  
Vol 12 ◽  
Author(s):  
Ágata C. Cevey ◽  
Paula D. Mascolo ◽  
Federico N. Penas ◽  
Azul V. Pieralisi ◽  
Aldana S. Sequeyra ◽  
...  
Keyword(s):  
Cell Line ◽  
Chagas Disease ◽  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Macrophage Polarization ◽  
Catalytic Subunit ◽  
M2 Macrophage ◽  
Socs3 Expression ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Benznidazole (Bzl), the drug of choice in many countries for the treatment of Chagas disease, leads to parasite clearance in the early stages of infection and contributes to immunomodulation. In addition to its parasiticidal effect, Bzl inhibits the NF-κB pathway. In this regard, we have previously described that this occurs through IL-10/STAT3/SOCS3 pathway. PI3K pathway is involved in the regulation of the immune system by inhibiting NF-κB pathway through STAT3. In this work, the participation of PI3K in the immunomodulatory effects of Bzl in cardiac and immune cells, the main targets of Chagas disease, was further studied. For that, we use a murine primary cardiomyocyte culture and a monocyte/macrophage cell line (RAW 264.7), stimulated with LPS in presence of LY294002, an inhibitor of PI3K. Under these conditions, Bzl could neither increase SOCS3 expression nor inhibit the NOS2 mRNA expression and the release of NOx, both in cardiomyocytes and macrophages. Macrophages are crucial in the development of Chronic Chagas Cardiomyopathy. Thus, to deepen our understanding of how Bzl acts, the expression profile of M1-M2 macrophage markers was evaluated. Bzl inhibited the release of NOx (M1 marker) and increased the expression of Arginase I (M2 marker) and a negative correlation was found between them. Besides, LPS increased the expression of pro-inflammatory cytokines. Bzl treatment not only inhibited this effect but also increased the expression of typical M2-macrophage markers like Mannose Receptor, TGF-β, and VEGF-A. Moreover, Bzl increased the expression of PPAR-γ and PPAR-α, known as key regulators of macrophage polarization. PI3K directly regulates M1-to-M2 macrophage polarization. Since p110δ, catalytic subunit of PI3Kδ, is highly expressed in immune cells, experiments were carried out in presence of CAL-101, a specific inhibitor of this subunit. Under this condition, Bzl could neither increase SOCS3 expression nor inhibit NF-κB pathway. Moreover, Bzl not only failed to inhibit the expression of pro-inflammatory cytokines (M1 markers) but also could not increase M2 markers. Taken together these results demonstrate, for the first time, that the anti-inflammatory effect of Bzl depends on PI3K activity in a cell line of murine macrophages and in primary culture of neonatal cardiomyocytes. Furthermore, Bzl-mediated increase expression of M2-macrophage markers involves the participation of the p110δ catalytic subunit of PI3Kδ.

scholarly journals Roles of Pro- and Anti-Inflammatory Cytokines in the Pathogenesis of SLE

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Ding-Lei Su ◽  
Zhi-Min Lu ◽  
Min-Ning Shen ◽  
Xia Li ◽  
Ling-Yun Sun
Keyword(s):  
Complex Network ◽  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Inflammatory Disease ◽  
Immune Homeostasis ◽  
Adaptive Immune ◽  
Adaptive Immune Cells ◽  
Autoimmune Inflammatory Disease ◽  
Anti Inflammatory

SLE is an autoimmune inflammatory disease in which various pro- and anti-inflammatory cytokines, including TGF-β, IL-10, BAFF, IL-6, IFN-α, IFN-γ, IL-17, and IL-23, play crucial pathogenic roles. Virtually, all these cytokines can be generated by both innate and adaptive immune cells and exert different effects depending on specific local microenvironment. They can also interact with each other, forming a complex network to maintain delicate immune homeostasis. In this paper, we elaborate on the abnormal secretion and functions of these cytokines in SLE, analyze their potential pathogenic roles, and probe into the possibility of them being utilized as targets for therapy.

scholarly journals Omega-3 polyunsaturated fatty acids and the inflammatory state of the Caco-2 gut epithelium model

2020 ◽  
Vol 79 (OCE2) ◽  
Author(s):  
Luke Durkin ◽  
Caroline Childs ◽  
Philip Calder
Keyword(s):  
Fatty Acids ◽  
Polyunsaturated Fatty Acids ◽  
Tight Junction ◽  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Paracellular Permeability ◽  
Omega 3 ◽  
Gut Epithelium ◽  
Anti Inflammatory

AbstractThe gut epithelium is a protective interface between the external environment and the human body. This epithelium interacts with a multitude of internal stimuli from the bloodstream and immune cells, and luminal stimuli from microorganisms and the diet. Disruptions to the epithelium are seen in inflammatory bowel diseases and coeliac disease. The human adenocarcinoma cell line (Caco-2) is an in vitro model used to assess the interactions between nutrients and gut epithelium. Long-chain omega-3 (n-3) polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have anti-inflammatory effects via the production of anti-inflammatory eicosanoids, interactions with immune cells and reductions in pro-inflammatory cytokines and chemokines. The aim of this study is to assess the anti-inflammatory properties of DHA and EPA in stimulated Caco-2 monolayers. Caco-2 cells were seeded at 70,000 cells/cm2 and grown to confluence before being allowed to fully differentiate (approx. 21 days total). Cytokines (TNF-α, IFN-γ, and IL-1β) and peptic-tryptic (PT-) gliadin were used as inflammatory stimulants. EPA and DHA incubations occurred 48 hours pre-stimulation. Tight junction function and morphology was determined using trans-epithelial electrical resistance measurements and confocal microscopy. Inflammatory markers, including IL-6, IL-8, and IL-17, were assessed by multiplex. Stimulatory cytokines induced tight junction dysfunction and increased pro-inflammatory mediator production in Caco-2 cells. PT-gliadin, DHA and EPA treatment did not alter paracellular permeability or stimulant-induced production of pro-inflammatory mediators. Further investigation of the inflammatory role of n-3 PUFAs and PT-gliadin in the Caco-2 model is required. Future work will assess the composition of PT-gliadin by electrophoresis and whether co-incubation of n-3 PUFAs and inflammatory cytokines will alter paracellular permeability and mediator output of Caco-2 cells.

scholarly journals Kallikrein-related peptidase 6 exacerbates disease in an autoimmune model of multiple sclerosis

2016 ◽  
Vol 397 (12) ◽  
pp. 1277-1286 ◽  
Author(s):  
Hyesook Yoon ◽  
Isobel A. Scarisbrick
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Systemic Administration ◽  
Neurological Deficits ◽  
Interleukin 17 ◽  
The Impact

Abstract Kallikrein-related peptidase 6 (Klk6) is elevated in the serum of multiple sclerosis (MS) patients and is hypothesized to participate in inflammatory and neuropathogenic aspects of the disease. To test this hypothesis, we investigated the impact of systemic administration of recombinant Klk6 on the development and progression of MOG35-55-induced experimental autoimmune encephalomyelitis (EAE). First, we determined that Klk6 expression is elevated in the spinal cord of mice with EAE at the peak of clinical disease and in immune cells upon priming with the disease-initiating peptide in vitro. Systemic administration of recombinant Klk6 to mice during the priming phase of disease resulted in an exacerbation of clinical symptoms, including earlier onset of disease and higher levels of spinal cord inflammation and pathology. Treatment of MOG35-55-primed immune cells with Klk6 in culture enhanced expression of pro-inflammatory cytokines, interferon-γ, tumor necrosis factor, and interleukin-17, while reducing anti-inflammatory cytokines interleukin-4 and interleukin-5. Together these findings provide evidence that elevations in systemic Klk6 can bias the immune system towards pro-inflammatory responses capable of exacerbating the development of neuroinflammation and paralytic neurological deficits. We suggest that Klk6 represents an important target for conditions in which pro-inflammatory responses play a critical role in disease development, including MS.

Abstract 444: Probiotic Administration Mitigates the Detrimental Effects of Myocardial Infarction in Mice

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
John Konhilas
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Cells ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Cardiac Injury ◽  
Cost Effective ◽  
Specific Strain ◽  
Anti Inflammatory ◽  
Microbial Environment

Advances in sequencing and bioinformatics technologies have allowed unprecedented characterization of the gut microbiome. As a result, there is a growing appreciation that our microbial environment plays a critical role in the maintenance of health and the pathogenesis of disease. Accordingly, recent evidence suggests a role for gut microbiota in modulating cardiovascular disease and cardiac injury. We hypothesized that administration of the probiotic, Bifidobacterium animalis subsp. lactis 420 (B420), to mice will mitigate the pathological impact of ischemic heart disease (IHD), and that anti-inflammatory T regulatory (T reg ) immune cells are necessary to impart protection against IHD as a result of B420 administration. Pretreatment with B420 for 14 or 35 days attenuated cardiac injury from ischemia/reperfusion or permanent coronary ligation. Infarcted hearts from B420 treated animals displayed a significant reduction in pro-inflammatory markers and an increase in anti-inflammatory regulatory T cells (T reg ). We further show that T reg immune cells are necessary players to communicate this protection by B420 administration. This protection is due, at least in part, to an increase in anti-inflammatory M2 type macrophages in B420 treated animals. These results suggest that administration of the probiotic B420 protects against cardiac injury and that regulatory T cells mediate this effect. Modulation of the inflammatory response by administration of a specific strain of probiotic may offer a rational, safe, and cost effective way to prevent inflammatory damage after cardiac injury.

Sign in / Sign up

Export Citation Format

Share Document