MicroRNAs in Immune Response and Macrophage Polarization

Paratuberculosis (PTB) is an enteric granulomatous disease caused by Mycobacterium avium subsp. paratuberculosis (MAP) that mainly affects ruminants. Current vaccines have shown to be cost–effective control reagents, although they are restricted due to cross-interference with bovine tuberculosis (bTB). Therefore, novel vaccination strategies are needed and this study is focused on evaluating alternative vaccination routes and their effect on the local immune response. The MAP oral challenge rabbit model was used to evaluate and compare an experimental inactivated MAP vaccine through oral (VOR) and intradermal (VID) routes. The VID group presented the highest proportion of animals with no visible lesions and the lowest proportion of animals with MAP positive tissues. Immunohistochemistry analysis revealed that the VID group presented a dominantly M1 polarized response indicating an ability to control MAP infection. In general, all vaccinated groups showed lower calprotectin levels compared to the non-vaccinated challenged group suggesting less active granulomatous lesions. The VID group showed some degree of skin test reactivity, whereas the same vaccine through oral administration was completely negative. These data show that PTB vaccination has an effect on macrophage polarization and that the route influences infection outcome and can also have an impact on bTB diagnosis. Future evaluation of new immunological products against mycobacterial diseases should consider assaying different vaccination routes.

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Dual-Wavelength Photosensitive Nano-in-Micro Scaffold Regulates Innate and Adaptive Immune Responses for Osteogenesis

Nano-Micro Letters ◽

10.1007/s40820-020-00540-z ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Qin Zhao ◽

Miusi Shi ◽

Chengcheng Yin ◽

Zifan Zhao ◽

Jinglun Zhang ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Immune Cells ◽

Inflammatory Responses ◽

Macrophage Polarization ◽

T Cell Response ◽

Dual Wavelength ◽

M2 Macrophage ◽

Adaptive Immune Responses ◽

Adaptive Immune

AbstractThe immune response of a biomaterial determines its osteoinductive effect. Although the mechanisms by which some immune cells promote regeneration have been revealed, the biomaterial-induced immune response is a dynamic process involving multiple cells. Currently, it is challenging to accurately regulate the innate and adaptive immune responses to promote osteoinduction in biomaterials. Herein, we investigated the roles of macrophages and dendritic cells (DCs) during the osteoinduction of biphasic calcium phosphate (BCP) scaffolds. We found that osteoinductive BCP directed M2 macrophage polarization and inhibited DC maturation, resulting in low T cell response and efficient osteogenesis. Accordingly, a dual-targeting nano-in-micro scaffold (BCP loaded with gold nanocage, BCP-GNC) was designed to regulate the immune responses of macrophages and DCs. Through a dual-wavelength photosensitive switch, BCP-GNC releases interleukin-4 in the early stage of osteoinduction to target M2 macrophages and then releases dexamethasone in the later stage to target immature DCs, creating a desirable inflammatory environment for osteogenesis. This study demonstrates that biomaterials developed to have specific regulatory capacities for immune cells can be used to control the early inflammatory responses of implanted materials and induce osteogenesis.

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Metabolic signatures linked to macrophage polarization: from glucose metabolism to oxidative phosphorylation

Biochemical Society Transactions ◽

10.1042/bst20150107 ◽

2015 ◽

Vol 43 (4) ◽

pp. 740-744 ◽

Cited By ~ 26

Author(s):

Lisardo Boscá ◽

Silvia González-Ramos ◽

Patricia Prieto ◽

María Fernández-Velasco ◽

Marina Mojena ◽

...

Keyword(s):

Immune Response ◽

Energy Metabolism ◽

Glucose Metabolism ◽

Oxidative Phosphorylation ◽

Metabolic Activity ◽

Functional Role ◽

Macrophage Activation ◽

Macrophage Polarization ◽

M1 Polarization ◽

Different Types

Macrophages are present in a large variety of locations, playing distinct functions that are determined by its developmental origin and by the nature of the activators of the microenvironment. Macrophage activation can be classified as pro-inflammatory (M1 polarization) or anti-inflammatory-pro-resolution-deactivation (M2), these profiles coexisting in the course of the immune response and playing a relevant functional role in the onset of inflammation (Figure 1). Several groups have analysed the metabolic aspects associated with macrophage activation to answer the question about what changes in the regulation of energy metabolism and biosynthesis of anabolic precursors accompany the different types of polarization and to what extent they are necessary for the expression of the activation phenotypes. The interest of these studies is to regulate macrophage function by altering their metabolic activity in a ‘therapeutic way’.

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Street RABV Induces the Cholinergic Anti-inflammatory Pathway in Human Monocyte-Derived Macrophages by Binding to nAChr α7

Frontiers in Immunology ◽

10.3389/fimmu.2021.622516 ◽

2021 ◽

Vol 12 ◽

Author(s):

Carmen W. E. Embregts ◽

Lineke Begeman ◽

Cees J. Voesenek ◽

Byron E. E. Martina ◽

Marion P. G. Koopmans ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Macrophage Polarization ◽

Flow Cytometric Analysis ◽

Human Monocyte ◽

Host Immune System ◽

Inflammatory Pathway ◽

Anti Inflammatory ◽

Alpha Bungarotoxin

Rabies virus (RABV) is able to reach the central nervous system (CNS) without triggering a strong immune response, using multiple mechanisms to evade and suppress the host immune system. After infection via a bite or scratch from a rabid animal, RABV comes into contact with macrophages, which are the first antigen-presenting cells (APCs) that are recruited to the area and play an essential role in the onset of a specific immune response. It is poorly understood how RABV affects macrophages, and if the interaction contributes to the observed immune suppression. This study was undertaken to characterize the interactions between RABV and human monocyte-derived macrophages (MDMs). We showed that street RABV does not replicate in human MDMs. Using a recombinant trimeric RABV glycoprotein (rRABV-tG) we showed binding to the nicotinic acetylcholine receptor alpha 7 (nAChr α7) on MDMs, and confirmed the specificity using the nAChr α7 antagonist alpha-bungarotoxin (α-BTX). We found that this binding induced the cholinergic anti-inflammatory pathway (CAP), characterized by a significant decrease in tumor necrosis factor α (TNF-α) upon LPS challenge. Using confocal microscopy we found that induction of the CAP is associated with significant cytoplasmic retention of nuclear factor κB (NF-κB). Co-cultures of human MDMs exposed to street RABV and autologous T cells further revealed that the observed suppression of MDMs might affect their function as T cell activators as well, as we found a significant decrease in proliferation of CD8+ T cells and an increased production of the anti-inflammatory cytokine IL-10. Lastly, using flow cytometric analysis we observed a significant increase in expression of the M2-c surface marker CD163, hinting that street RABV might be able to affect macrophage polarization. Taken together, these results show that street RABV is capable of inducing an anti-inflammatory state in human macrophages, possibly affecting T cell functioning.

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Harnessing the immune response to improve functional healing

Science Translational Medicine ◽

10.1126/scitranslmed.aav3889 ◽

2018 ◽

Vol 10 (463) ◽

pp. eaav3889 ◽

Cited By ~ 3

Author(s):

Julianne L. Holloway

Keyword(s):

Immune Response ◽

Gold Nanoparticles ◽

Mouse Model ◽

Macrophage Polarization ◽

Interleukin 4 ◽

M2 Macrophage ◽

Muscle Recovery ◽

M2 Macrophage Polarization

Interleukin-4–conjugated gold nanoparticles promote M2 macrophage polarization and functional muscle recovery in an ischemic mouse model.

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MiR-146a rs2910164 G > C polymorphism modulates Notch-1/IL-6 signaling during infection: a possible risk factor for Crohn’s disease

Gut Pathogens ◽

10.1186/s13099-020-00387-0 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Esra’a Keewan ◽

Saleh A. Naser

Keyword(s):

Immune Response ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Macrophage Polarization ◽

Statistical Significance ◽

Clinical Samples ◽

Healthy Controls ◽

Notch 1 ◽

Blood Samples ◽

The Impact

Abstract Background MiR-146a, an effector mediator, targets Notch-1 and regulates the innate and adaptive immune systems response. Recently, we reported that Notch-1 signaling plays a key role in macrophage polarization and response during infection. We employed Mycobacterium avium paratuberculosis (MAP) infection in Crohn’s disease (CD) as a model to demonstrate the role of Notch-1/IL-6 signaling on MCL-1 based apoptosis and intracellular MAP infection and persistence. This study was designed to investigate the impact of polymorphisms in miR146a on the immune response and infection in our MAP-CD model. Methods We determined the incidence of miR-146a rs2910164 G > C in 42 blood samples from clinical CD patients and controls. We also measured the effect of rs2910164 on expression of Notch-1 and IL-6, and plasma IL-6 protein levels in our study group. Finally, we analyzed the blood samples for MAP DNA and studied any correlation with miR-146a polymorphism. Samples were analyzed for statistical significance using unpaired tow-tailed t-test, unpaired two-tailed z-score and odds ratio. P < 0.05 considered significant. Results MiR-146a rs2910164 GC was detected at a higher incidence in CD (52.6%) compared to healthy controls (21.7%) rs2910164 GC Heterozygous polymorphism upregulated Notch-1 and IL-6, by 0.9 and 1.7-fold, respectively. As expected, MAP infection was detected more in CD samples (63%) compared to healthy controls (9%). Surprisingly, MAP infection was detected at a higher rate in samples with rs2910164 GC (67%) compared to samples with normal genotype (33%). Conclusions The data clearly associates miR-146a rs2910164 GC with an overactive immune response and increases the risk to acquire infection. The study is even more relevant now in our efforts to understand susceptibility to SARS-CoV-2 infection and the development of COVID-19. This study suggests that genetic variations among COVID-19 patients may predict who is at a higher risk of acquiring infection, developing exacerbating symptoms, and possibly death. A high scale study with more clinical samples from different disease groups is planned.

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Lipopolysaccharide triggers different transcriptional signatures in taurine and indicine cattle macrophages: Reactive oxygen species and potential outcomes to the development of immune response to infections

PLoS ONE ◽

10.1371/journal.pone.0241861 ◽

2020 ◽

Vol 15 (11) ◽

pp. e0241861

Author(s):

Raquel Morais de Paiva Daibert ◽

Carlos Alberto Oliveira de Biagi Junior ◽

Felipe de Oliveira Vieira ◽

Marcos Vinicius Gualberto Barbosa da Silva ◽

Eugenio Damaceno Hottz ◽

...

Keyword(s):

Gene Expression ◽

Nitric Oxide ◽

Immune Response ◽

Inflammatory Responses ◽

Macrophage Polarization ◽

Experimental Models ◽

Buffy Coat ◽

Nf Kappa B ◽

Amyloid A ◽

Nitric Oxide Concentration

Macrophages are classified upon activation as classical activated M1 and M2 anti-inflammatory regulatory populations. This macrophage polarization is well characterized in humans and mice, but M1/M2 profile in cattle has been far less explored. Bos primigenius taurus (taurine) and Bos primigenius indicus (indicine) cattle display contrasting levels of resistance to infection and parasitic diseases such as C57BL/6J and Balb/c murine experimental models of parasite infection outcomes based on genetic background. Thus, we investigated the differential gene expression profile of unstimulated and LPS stimulated monocyte-derived macrophages (MDMs) from Holstein (taurine) and Gir (indicine) breeds using RNA sequencing methodology. For unstimulated MDMs, the contrast between Holstein and Gir breeds identified 163 Differentially Expressed Genes (DEGs) highlighting the higher expression of C-C chemokine receptor type five (CCR5) and BOLA-DQ genes in Gir animals. LPS-stimulated MDMs from Gir and Holstein animals displayed 1,257 DEGs enriched for cell adhesion and inflammatory responses. Gir MDMs cells displayed a higher expression of M1 related genes like Nitric Oxide Synthase 2 (NOS2), Toll like receptor 4 (TLR4), Nuclear factor NF-kappa-B 2 (NFKB2) in addition to higher levels of transcripts for proinflammatory cytokines, chemokines, complement factors and the acute phase protein Serum Amyloid A (SAA). We also showed that gene expression of inflammatory M1 population markers, complement and SAA genes was higher in Gir in buffy coat peripheral cells in addition to nitric oxide concentration in MDMs supernatant and animal serum. Co-expression analyses revealed that Holstein and Gir animals showed different transcriptional signatures in the MDMs response to LPS that impact on cell cycle regulation, leukocyte migration and extracellular matrix organization biological processes. Overall, the results suggest that Gir animals show a natural propensity to generate a more pronounced M1 inflammatory response than Holstein, which might account for a faster immune response favouring resistance to many infection diseases.

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Modulation of Macrophage Phenotype by Biodegradable Polyurethane Nanoparticles: Possible Relation between Macrophage Polarization and Immune Response of Nanoparticles

ACS Applied Materials & Interfaces ◽

10.1021/acsami.8b04718 ◽

2018 ◽

Vol 10 (23) ◽

pp. 19436-19448 ◽

Cited By ~ 24

Author(s):

Yen-Jang Huang ◽

Kun-Che Hung ◽

Huey-Shan Hung ◽

Shan-hui Hsu

Keyword(s):

Immune Response ◽

Macrophage Polarization ◽

Macrophage Phenotype ◽

Biodegradable Polyurethane

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Cellular response of blood-borne immune cells to PEEU fiber meshes

Clinical Hemorheology and Microcirculation ◽

10.3233/ch-219114 ◽

2021 ◽

Vol 79 (1) ◽

pp. 205-216

Author(s):

Janita A. Maring ◽

Matthias Becker ◽

Wing Tai Tung ◽

Christof Stamm ◽

Nan Ma ◽

...

Keyword(s):

Immune Response ◽

Immune Cells ◽

Peripheral Blood ◽

Cellular Response ◽

Mononuclear Cells ◽

Macrophage Polarization ◽

T Cell Proliferation ◽

Cytokine Release ◽

Tnf Α ◽

Activated Monocytes

BACKGROUND: Polymeric materials have been widely used as artificial grafts in cardiovascular applications. These polymeric implants can elicit a detrimental innate and adaptive immune response after interacting with peripheral blood. A surface modification with components from extracellular matrices (ECM) may minimize the activation of immune cells from peripheral blood. The aim of this study is to compare the cellular response of blood-born immune cells to the fiber meshes from polyesteretherurethane (PEEUm) and PEEUm with ECM coating (PEEUm + E). MATERIALS AND METHODS: Electrospun PEEUm were used as-is or coated with human cardiac ECM. Different immune cells were isolated form human peripheral blood. Cytokine release profile from naïve and activated monocytes was assessed. Macrophage polarization and T cell proliferation, as indication of immune response were evaluated. RESULTS: There was no increase in cytokine release (IL-6, TNF-α, and IL-10) from activated monocytes, macrophages and mononuclear cells on PEEUm; neither upon culturing on PEEUm + E. Naïve monocytes showed increased levels of IL-6 and TNF-α, which were not present on PEEUm + E. There was no difference on monocyte derived macrophage polarization towards pro-inflammatory M1 or anti-inflammatory M2 on PEEUm and PEEUm + E. Moreover, T cell proliferation was not increased upon interacting with PEEUm directly. CONCLUSION: As PEEUm only elicits a minimal response from naïve monocytes but not from monocytes, peripheral blood mononuclear cells (PBMCs) or T cells, the slight improvement in response to PEEUm + E might not justify the additional effort of coating with a human ECM.

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