Anti-infection roles of miR-155-5p packaged in exosomes secreted by dendritic cells infected with Toxoplasma gondii

Abstract Background Toxoplasma gondii is a zoonotic intracellular protozoon that is estimated to infect about 30% of the world’s population, resulting in toxoplasmosis in immunocompromised patients and adverse outcomes in cases of primary infection during pregnancy. Exosomes are tubular vesicles secreted by cells, and function in intercellular communication. It has been reported that the exosomes secreted by T. gondii-infected immune cells transmit infection signals to the uninfected cells. However, the mechanism and effect of the exosome transmission are still vague. We therefore investigated the function of the exosomes transmitted from DC2.4 cells infected with the T. gondii RH strain (Tg-DC-Exo) to the uninfected cells, as well as their roles in anti-infection. Methods We conducted exosome isolation and identification with ultracentrifugation, transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blot (WB) analysis. Exosome uptake by recipient cells was identified by PKH67 assay. The signal transmission and the abundance of miR-155-5p were determined using transwell assay and qRT-PCR. For detection of immune responses, cytokine secretion was evaluated. The T. gondii B1 gene was determined to evaluate tachyzoite proliferation. Results We observed that Toxoplasma infection upregulated miR-155-5p expression in DC2.4 cell-secreted exosomes, and those exosomes could be ingested by murine macrophage RAW264.7 cells. Tg-DC-Exo and miR-155-5p stimulated host proinflammatory immune responses including increased production of proinflammatory cytokines IL-6 and TNF-α, and proinflammatory marker-inducible nitric oxide synthase (iNOS). The NF-κB pathway was activated by downregulation of SOCS1, leading to inhibition of T. gondii tachyzoite proliferation in RAW264.7 cells. Conclusions Our findings provide a novel mechanism for how infected cells transmit infection signals to the uninfected cells through exosome secretion after T. gondii infection, followed by inflammatory responses and anti-infection reactions, which may help us develop a new strategy for toxoplasmosis prevention, especially in immunocompromised patients. Graphical Abstract

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Anti-Infection Roles of mir155-5p Packaged in Exosomes Secreted by Dendritic Cells Infected with Toxoplasma Gondii

10.21203/rs.3.rs-287510/v1 ◽

2021 ◽

Author(s):

Dan Jiang ◽

Shuizhen Wu ◽

Liqing Xu ◽

Guantai Xie ◽

Hong-Juan Peng

Keyword(s):

Toxoplasma Gondii ◽

Immune Responses ◽

Inflammatory Responses ◽

Signal Transmission ◽

Intervention Strategy ◽

Adverse Outcomes ◽

Raw264.7 Cells ◽

Isolation And Identification ◽

Pathway Activation ◽

Compromised Patients

Abstract Background: Toxoplasma gondii is a zoonotic intracellular protozoon that is estimated to infect about 30% of the world’s population, resulting in toxoplasmosis in immuno-compromised patients and adverse outcomes in the primary infection during pregnancy. Exosomes are tubular vesicles secreted by cells, and they function in intercellular communication. It has been reported that the exosomes secreted by T. gondii-infected immune cells transmit infection signals to the uninfected cells. However, the mechanism and effect of the exosome transmission are still vague. We therefore investigated the function of the exosomes transmitted from DC2.4 cells infected with T. gondii RH strain (Tg-DC-Exo) to the uninfected cells, as well as their roles in anti-infection. Methods: We conducted exosome isolation and identification with ultracentrifugation, transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and Western blotting. Recipient cells taken up exosomes by PKH67 assay. The signal transmission and the abundance of mir155-5p were determined using transwell assay and qRT-PCR. For the immune responses, cytokines was evaluated. T. gondii B1 gene was determined to evaluate tachyzoites proliferation.Results: We observed that Toxoplasma infection up-regulated mir155-5p expression in DC2.4 cells secreted exosomes, and those exosomes can be ingested by murine macrophage RAW264.7 cells. Tg-DC-Exo and mir155-5p stimulating host proinflammatory immune responses such as proinflammatory cytokine (IL6,iNOS and TNF-α) production increased and NF-κB signal pathway activation by down regulating SOCS1, leading to inhibit T. gondii tachyzoite proliferation in RAW264.7 cells. Conclusion: Our findings provide a novel mechanism for how infected cells transmit infection signals to the uninfected cells through exosome secretion after T. gondii infection, followed by inflammatory responses and anti-infection reactions, which may help us develop a new intervention strategy for toxoplasmosis prevention, especially in immuno-compromised patients.

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Immunosuppressive Mechanisms of Regulatory B Cells

Frontiers in Immunology ◽

10.3389/fimmu.2021.611795 ◽

2021 ◽

Vol 12 ◽

Author(s):

Diego Catalán ◽

Miguel Andrés Mansilla ◽

Ashley Ferrier ◽

Lilian Soto ◽

Kristine Oleinika ◽

...

Keyword(s):

B Cells ◽

Immune Responses ◽

Metabolic Diseases ◽

Inflammatory Responses ◽

Surface Proteins ◽

Regulatory B Cells ◽

Cell Surface Proteins ◽

The Past ◽

And Function

Regulatory B cells (Bregs) is a term that encompasses all B cells that act to suppress immune responses. Bregs contribute to the maintenance of tolerance, limiting ongoing immune responses and reestablishing immune homeostasis. The important role of Bregs in restraining the pathology associated with exacerbated inflammatory responses in autoimmunity and graft rejection has been consistently demonstrated, while more recent studies have suggested a role for this population in other immune-related conditions, such as infections, allergy, cancer, and chronic metabolic diseases. Initial studies identified IL-10 as the hallmark of Breg function; nevertheless, the past decade has seen the discovery of other molecules utilized by human and murine B cells to regulate immune responses. This new arsenal includes other anti-inflammatory cytokines such IL-35 and TGF-β, as well as cell surface proteins like CD1d and PD-L1. In this review, we examine the main suppressive mechanisms employed by these novel Breg populations. We also discuss recent evidence that helps to unravel previously unknown aspects of the phenotype, development, activation, and function of IL-10-producing Bregs, incorporating an overview on those questions that remain obscure.

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IL-37 (IL-1F7) the Newest Anti-Inflammatory Cytokine Which Suppresses Immune Responses and Inflammation

International Journal of Immunopathology and Pharmacology ◽

10.1177/039463201202500105 ◽

2012 ◽

Vol 25 (1) ◽

pp. 31-38 ◽

Cited By ~ 43

Author(s):

S. Tetè ◽

D. Tripodi ◽

M. Rosati ◽

F. Conti ◽

G. Maccauro ◽

...

Keyword(s):

Epithelial Cells ◽

Immune Responses ◽

Proinflammatory Cytokines ◽

Mechanism Of Action ◽

Inflammatory Cytokine ◽

Inflammatory Responses ◽

Detailed Mechanism ◽

Anti Inflammatory ◽

And Function ◽

Anti Inflammatory Cytokine

Cytokines such as interleukins, chemokines and interferons are immunomodulating and inflammatory agents, characterized by considerable redundancy, in that many cytokines appear to share similar functions. Virtually all nucleated cells, but especially epithelial cells and macrophages, are potent producers of cytokines. The objective of this study is to review the detailed mechanism of action and the biological profiles of IL-37, the newest anti-inflammatory cytokine. This review focuses on IL-37, a key cytokine in regulating inflammatory responses, mainly by inhibiting the expression, production and function of proinflammatory cytokines: IL-1 family pro-inflammatory effects are markedly suppressed by IL-37.

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MicroRNAs and Multiple Sclerosis

Autoimmune Diseases ◽

10.4061/2011/807426 ◽

2011 ◽

Vol 2011 ◽

pp. 1-27 ◽

Cited By ~ 16

Author(s):

Kemal Ugur Tufekci ◽

Meryem Gulfem Oner ◽

Sermin Genc ◽

Kursad Genc

Keyword(s):

Multiple Sclerosis ◽

Immune Responses ◽

Inflammatory Responses ◽

Current Knowledge ◽

Expression Patterns ◽

Mirna Biogenesis ◽

Disease Marker ◽

Organ Specific ◽

And Function

MicroRNAs (miRNAs) have recently emerged as a new class of modulators of gene expression. miRNAs control protein synthesis by targeting mRNAs for translational repression or degradation at the posttranscriptional level. These noncoding RNAs are endogenous, single-stranded molecules approximately 22 nucleotides in length and have roles in multiple facets of immunity, from regulation of development of key cellular players to activation and function in immune responses. Recent studies have shown that dysregulation of miRNAs involved in immune responses leads to autoimmunity. Multiple sclerosis (MS) serves as an example of a chronic and organ-specific autoimmune disease in which miRNAs modulate immune responses in the peripheral immune compartment and the neuroinflammatory process in the brain. For MS, miRNAs have the potential to serve as modifying drugs. In this review, we summarize current knowledge of miRNA biogenesis and mode of action and the diverse roles of miRNAs in modulating the immune and inflammatory responses. We also review the role of miRNAs in autoimmunity, focusing on emerging data regarding miRNA expression patterns in MS. Finally, we discuss the potential of miRNAs as a disease marker and a novel therapeutic target in MS. Better understanding of the role of miRNAs in MS will improve our knowledge of the pathogenesis of this disease.

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Interleukin-10 and Immunity against Prokaryotic and Eukaryotic Intracellular Pathogens

Infection and Immunity ◽

10.1128/iai.00047-11 ◽

2011 ◽

Vol 79 (8) ◽

pp. 2964-2973 ◽

Cited By ~ 123

Author(s):

Joshua C. Cyktor ◽

Joanne Turner

Keyword(s):

Immune Response ◽

Immune Responses ◽

Inflammatory Responses ◽

Interleukin 10 ◽

Parasitic Infections ◽

Intracellular Pathogens ◽

Effective Immune Response ◽

Infection Models ◽

And Function

ABSTRACTThe generation of an effective immune response against an infection while also limiting tissue damage requires a delicate balance between pro- and anti-inflammatory responses. Interleukin-10 (IL-10) has potent immunosuppressive effects and is essential for regulation of immune responses. However, the immunosuppressive properties of IL-10 can also be exploited by pathogens to facilitate their own survival. In this minireview, we discuss the role of IL-10 in modulating intracellular bacterial, fungal, and parasitic infections. Using information from several different infection models, we bring together and highlight some common pathways for IL-10 regulation and function that cannot be fully appreciated by studies of a single pathogen.

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Secreted Effectors Modulating Immune Responses to Toxoplasma gondii

Life ◽

10.3390/life11090988 ◽

2021 ◽

Vol 11 (9) ◽

pp. 988

Author(s):

Tadakimi Tomita ◽

Rebekah B. Guevara ◽

Lamisha M. Shah ◽

Andrews Y. Afrifa ◽

Louis M. Weiss

Keyword(s):

Toxoplasma Gondii ◽

Immune Responses ◽

Inflammatory Responses ◽

Parasitophorous Vacuole ◽

Congenital Infection ◽

Dense Granule ◽

Obligate Intracellular ◽

Host Cytoplasm ◽

Life Threatening ◽

Intracellular Milieu

Toxoplasma gondii is an obligate intracellular parasite that chronically infects a third of humans. It can cause life-threatening encephalitis in immune-compromised individuals. Congenital infection also results in blindness and intellectual disabilities. In the intracellular milieu, parasites encounter various immunological effectors that have been shaped to limit parasite infection. Parasites not only have to suppress these anti-parasitic inflammatory responses but also ensure the host organism’s survival until their subsequent transmission. Recent advancements in T. gondii research have revealed a plethora of parasite-secreted proteins that suppress as well as activate immune responses. This mini-review will comprehensively examine each secreted immunomodulatory effector based on the location of their actions. The first section is focused on secreted effectors that localize to the parasitophorous vacuole membrane, the interface between the parasites and the host cytoplasm. Murine hosts are equipped with potent IFNγ-induced immune-related GTPases, and various parasite effectors subvert these to prevent parasite elimination. The second section examines several cytoplasmic and ER effectors, including a recently described function for matrix antigen 1 (MAG1) as a secreted effector. The third section covers the repertoire of nuclear effectors that hijack transcription factors and epigenetic repressors that alter gene expression. The last section focuses on the translocation of dense-granule effectors and effectors in the setting of T. gondii tissue cysts (the bradyzoite parasitophorous vacuole).

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Matrix Metalloproteinases in Invertebrates

Protein and Peptide Letters ◽

10.2174/0929866527666200429110945 ◽

2020 ◽

Vol 27 (11) ◽

pp. 1068-1081

Author(s):

Xi Liu ◽

Dongwu Liu ◽

Yangyang Shen ◽

Mujie Huang ◽

Lili Gao ◽

...

Keyword(s):

Matrix Metalloproteinases ◽

Immune Responses ◽

Theoretical Basis ◽

Regulatory Mechanism ◽

Structure And Function ◽

Catalytic Domains ◽

Physiological Processes ◽

Disease Occurrence ◽

Complex Functions ◽

And Function

Matrix Metalloproteinases (MMPs) belong to a family of metal-dependent endopeptidases which contain a series of conserved pro-peptide domains and catalytic domains. MMPs have been widely found in plants, animals, and microorganisms. MMPs are involved in regulating numerous physiological processes, pathological processes, and immune responses. In addition, MMPs play a key role in disease occurrence, including tumors, cardiovascular diseases, and other diseases. Compared with invertebrate MMPs, vertebrate MMPs have diverse subtypes and complex functions. Therefore, it is difficult to study the function of MMPs in vertebrates. However, it is relatively easy to study invertebrate MMPs because there are fewer subtypes of MMPs in invertebrates. In the present review, the structure and function of MMPs in invertebrates were summarized, which will provide a theoretical basis for investigating the regulatory mechanism of MMPs in invertebrates.

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Adaptive metabolic and inflammatory responses identified using accelerated aging metrics are linked to adverse outcomes in severe SARS-CoV-2 infection

The Journals of Gerontology Series A ◽

10.1093/gerona/glab078 ◽

2021 ◽

Author(s):

Alejandro Márquez-Salinas ◽

Carlos A Fermín-Martínez ◽

Neftalí Eduardo Antonio-Villa ◽

Arsenio Vargas-Vázquez ◽

Enrique C. Guerra ◽

...

Keyword(s):

Critical Illness ◽

Proportional Hazards ◽

Inflammatory Responses ◽

Age Groups ◽

Accelerated Aging ◽

Cox Proportional Hazards ◽

Adverse Outcomes ◽

Adaptive Responses ◽

Predictive Capacity ◽

Risk Of Death

Abstract Background Chronological age (CA) is a predictor of adverse COVID-19 outcomes; however, CA alone does not capture individual responses to SARS-CoV-2 infection. Here, we evaluated the influence of aging metrics PhenoAge and PhenoAgeAccel to predict adverse COVID-19 outcomes. Furthermore, we sought to model adaptive metabolic and inflammatory responses to severe SARS-CoV-2 infection using individual PhenoAge components. Methods In this retrospective cohort study, we assessed cases admitted to a COVID-19 reference center in Mexico City. PhenoAge and PhenoAgeAccel were estimated using laboratory values at admission. Cox proportional hazards models were fitted to estimate risk for COVID-19 lethality and adverse outcomes (ICU admission, intubation, or death). To explore reproducible patterns which model adaptive responses to SARS-CoV-2 infection, we used k-means clustering using PhenoAge components. Results We included 1068 subjects of whom 222 presented critical illness and 218 died. PhenoAge was a better predictor of adverse outcomes and lethality compared to CA and SpO2 and its predictive capacity was sustained for all age groups. Patients with responses associated to PhenoAgeAccel>0 had higher risk of death and critical illness compared to those with lower values (log-rank p<0.001). Using unsupervised clustering we identified four adaptive responses to SARS-CoV-2 infection: 1) Inflammaging associated with CA, 2) metabolic dysfunction associated with cardio-metabolic comorbidities, 3) unfavorable hematological response, and 4) response associated with favorable outcomes. Conclusions Adaptive responses related to accelerated aging metrics are linked to adverse COVID-19 outcomes and have unique and distinguishable features. PhenoAge is a better predictor of adverse outcomes compared to CA.

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Pattern of inflammatory immune response determines the clinical course and outcome of COVID-19: unbiased clustering analysis

Scientific Reports ◽

10.1038/s41598-021-87668-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Eunyoung Emily Lee ◽

Kyoung-Ho Song ◽

Woochang Hwang ◽

Sin Young Ham ◽

Hyeonju Jeong ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Clustering Analysis ◽

Validation Cohort ◽

Inflammatory Responses ◽

Clinical Course ◽

Severe Disease ◽

Outcome Data ◽

Inflammatory Immune Response ◽

Cluster 2

AbstractThe objective of the study was to identify distinct patterns in inflammatory immune responses of COVID-19 patients and to investigate their association with clinical course and outcome. Data from hospitalized COVID-19 patients were retrieved from electronic medical record. Supervised k-means clustering of serial C-reactive protein levels (CRP), absolute neutrophil counts (ANC), and absolute lymphocyte counts (ALC) was used to assign immune responses to one of three groups. Then, relationships between patterns of inflammatory responses and clinical course and outcome of COVID-19 were assessed in a discovery and validation cohort. Unbiased clustering analysis grouped 105 patients of a discovery cohort into three distinct clusters. Cluster 1 (hyper-inflammatory immune response) was characterized by high CRP levels, high ANC, and low ALC, whereas Cluster 3 (hypo-inflammatory immune response) was associated with low CRP levels and normal ANC and ALC. Cluster 2 showed an intermediate pattern. All patients in Cluster 1 required oxygen support whilst 61% patients in Cluster 2 and no patient in Cluster 3 required supplementary oxygen. Two (13.3%) patients in Cluster 1 died, whereas no patient in Clusters 2 and 3 died. The results were confirmed in an independent validation cohort of 116 patients. We identified three different patterns of inflammatory immune response to COVID-19. Hyper-inflammatory immune responses with elevated CRP, neutrophilia, and lymphopenia are associated with a severe disease and a worse outcome. Therefore, targeting the hyper-inflammatory response might improve the clinical outcome of COVID-19.

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Molecular and phenotypic analysis of rodent models reveals conserved and species-specific modulators of human sarcopenia

Communications Biology ◽

10.1038/s42003-021-01723-z ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Anastasiya Börsch ◽

Daniel J. Ham ◽

Nitish Mittal ◽

Lionel A. Tintignac ◽

Eugenia Migliavacca ◽

...

Keyword(s):

Muscle Mass ◽

Inflammatory Responses ◽

Molecular Data ◽

Model Organisms ◽

Sequencing Data ◽

Phenotypic Analysis ◽

Age Related ◽

Analogous Data ◽

Species Specific ◽

And Function

AbstractSarcopenia, the age-related loss of skeletal muscle mass and function, affects 5–13% of individuals aged over 60 years. While rodents are widely-used model organisms, which aspects of sarcopenia are recapitulated in different animal models is unknown. Here we generated a time series of phenotypic measurements and RNA sequencing data in mouse gastrocnemius muscle and analyzed them alongside analogous data from rats and humans. We found that rodents recapitulate mitochondrial changes observed in human sarcopenia, while inflammatory responses are conserved at pathway but not gene level. Perturbations in the extracellular matrix are shared by rats, while mice recapitulate changes in RNA processing and autophagy. We inferred transcription regulators of early and late transcriptome changes, which could be targeted therapeutically. Our study demonstrates that phenotypic measurements, such as muscle mass, are better indicators of muscle health than chronological age and should be considered when analyzing aging-related molecular data.

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