scholarly journals STAT1-Dependent Recruitment of Ly6ChiCCR2+ Inflammatory Monocytes and M2 Macrophages in a Helminth Infection

Pathogens ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1287
Author(s):  
Mireya Becerra-Díaz ◽  
Yadira Ledesma-Soto ◽  
Jonadab E. Olguín ◽  
Angel Sánchez-Barrera ◽  
Mónica G. Mendoza-Rodríguez ◽  
...  
Keyword(s):  
Post Infection ◽  
Viral Infections ◽  
Helminth Infection ◽  
Parasitic Infections ◽  
M2 Macrophages ◽  
Monocytic Cells ◽  
Alternatively Activated Macrophages ◽  
Inflammatory Monocytes ◽  
Th2 Cytokine

Signal Transducer and Activator of Transcription (STAT) 1 signaling is critical for IFN-γ-mediated immune responses and resistance to protozoan and viral infections. However, its role in immunoregulation during helminth parasitic infections is not fully understood. Here, we used STAT1−/− mice to investigate the role of this transcription factor during a helminth infection caused by the cestode Taenia crassiceps and show that STAT1 is a central molecule favoring susceptibility to this infection. STAT1−/− mice displayed lower parasite burdens at 8 weeks post-infection compared to STAT1+/+ mice. STAT1 mediated the recruitment of inflammatory monocytes and the development of alternatively activated macrophages (M2) at the site of infection. The absence of STAT1 prevented the recruitment of CD11b+Ly6ChiLy6G− monocytic cells and therefore their suppressive activity. This failure was associated with the defective expression of CCR2 on CD11b+Ly6ChiLy6G− cells. Importantly, CD11b+Ly6ChiLy6G− cells highly expressed PDL-1 and suppressed T-cell proliferation elicited by anti-CD3 stimulation. PDL-1+ cells were mostly absent in STAT1−/− mice. Furthermore, only STAT1+/+ mice developed M2 macrophages at 8 weeks post-infection, although macrophages from both T. crassiceps-infected STAT1+/+ and STAT1−/− mice responded to IL-4 in vitro, and both groups of mice were able to produce the Th2 cytokine IL-13. This suggests that CD11b+CCR2+Ly6ChiLy6G− cells give rise to M2 macrophages in this infection. In summary, a lack of STAT1 resulted in impaired recruitment of CD11b+CCR2+Ly6ChiLy6G− cells, failure to develop M2 macrophages, and increased resistance against T. crassiceps infection.

scholarly journals A Dual Role for Macrophages in Modulating Lung Tissue Damage/Repair during L2 Toxocara canis Infection

Pathogens ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 280 ◽  
Author(s):  
Berenice Faz-López ◽  
Héctor Mayoral-Reyes ◽  
Rogelio Hernández-Pando ◽  
Pablo Martínez-Labat ◽  
Derek M. McKay ◽  
...  
Keyword(s):  
Lung Tissue ◽  
Tissue Damage ◽  
Tissue Repair ◽  
Inflammatory Responses ◽  
Parasitic Infection ◽  
Toxocara Canis ◽  
Parasitic Infections ◽  
Lung Pathology ◽  
M2 Macrophages ◽  
Alternatively Activated Macrophages

Macrophages that are classically activated (M1) through the IFN-γ/STAT1 signaling pathway have a major role in mediating inflammation during microbial and parasitic infections. In some cases, unregulated inflammation induces tissue damage. In helminth infections, alternatively activated macrophages (M2), whose activation occurs mainly via the IL-4/STAT6 pathway, have a major role in mediating protection against excessive inflammation, and has been associated with both tissue repair and parasite clearance. During the lung migratory stage of Toxocara canis, the roles of M1 and M2 macrophages in tissue repair remain unknown. To assess this, we orally infected wild-type (WT) and STAT1 and STAT6-deficient mice (STAT1−/− and STAT6−/−) with L2 T. canis, and evaluated the role of M1 or M2 macrophages in lung pathology. The absence of STAT1 favored an M2 activation pattern with Arg1, FIZZ1, and Ym1 expression, which resulted in parasite resistance and lung tissue repair. In contrast, the absence of STAT6 induced M1 activation and iNOS expression, which helped control parasitic infection but generated increased inflammation and lung pathology. Next, macrophages were depleted by intratracheally inoculating mice with clodronate-loaded liposomes. We found a significant reduction in alveolar macrophages that was associated with higher lung pathology in both WT and STAT1−/− mice; in contrast, STAT6−/− mice receiving clodronate-liposomes displayed less tissue damage, indicating critical roles of both macrophage phenotypes in lung pathology and tissue repair. Therefore, a proper balance between inflammatory and anti-inflammatory responses during T. canis infection is necessary to limit lung pathology and favor lung healing.

scholarly journals The Characterization of chIFITMs in Avian Coronavirus Infection In Vivo, Ex Vivo and In Vitro

Genes ◽  
2020 ◽  
Vol 11 (8) ◽  
pp. 918
Author(s):  
Angela Steyn ◽  
Sarah Keep ◽  
Erica Bickerton ◽  
Mark Fife
Keyword(s):  
Post Infection ◽  
Viral Infections ◽  
Ex Vivo ◽  
Large Family ◽  
Respiratory Pathogen ◽  
Restriction Factors ◽  
Respiratory Illnesses ◽  
Bird Mortality

The coronaviruses are a large family of enveloped RNA viruses that commonly cause gastrointestinal or respiratory illnesses in the infected host. Avian coronavirus infectious bronchitis virus (IBV) is a highly contagious respiratory pathogen of chickens that can affect the kidneys and reproductive systems resulting in bird mortality and decreased reproductivity. The interferon-inducible transmembrane (IFITM) proteins are activated in response to viral infections and represent a class of cellular restriction factors that restrict the replication of many viral pathogens. Here, we characterize the relative mRNA expression of the chicken IFITM genes in response to IBV infection, in vivo, ex vivo and in vitro using the pathogenic M41-CK strain, the nephropathogenic QX strain and the nonpathogenic Beaudette strain. In vivo we demonstrate a significant upregulation of chIFITM1, 2, 3 and 5 in M41-CK- and QX-infected trachea two days post-infection. In vitro infection with Beaudette, M41-CK and QX results in a significant upregulation of chIFITM1, 2 and 3 at 24 h post-infection. We confirmed a differential innate response following infection with distinct IBV strains and believe that our data provide new insights into the possible role of chIFITMs in early IBV infection.

scholarly journals The Anaphylatoxin C3a Receptor Expression on Human M2 Macrophages Is Down-Regulated by Stimulating the Histamine H4 Receptor and the IL-4 Receptor

2018 ◽  
Vol 10 (4) ◽  
pp. 349-362 ◽  
Author(s):  
Susanne Mommert ◽  
Derya Aslan ◽  
Lisanne Ratz ◽  
Holger Stark ◽  
Ralf Gutzmer ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Receptor Expression ◽  
M2 Macrophages ◽  
Histamine H4 Receptor ◽  
Th2 Cytokine ◽  
H4 Receptor ◽  
Differentiation Marker ◽  
Anaphylatoxin C3a ◽  
G Protein Coupled

The anaphylatoxin C3a triggers inflammation by binding to its specific G-protein-coupled C3a receptor (C3aR). Since the number of C3aR, which is expressed on the cell surface, affects the response to C3a, we investigated the expression levels of C3aR on human M2 macrophages in allergic situations where high levels of the Th2 cytokine IL-4 and histamine are present in a local microenvironment. The histamine H1 receptor (H1R), H2R and the H4R mRNA expressions were induced or up-regulated during the differentiation process of M2 macrophages. The presence of histamine or agonists targeting the H1R, H2R and, in particular, the H4R during in vitro differentiation from monocytes to macrophages modified the M2 phenotype by regulating the macrophage differentiation marker CD68 and CD163 expressions. In ­addition, the C3aR expression was also down-regulated by ­ST-1006 during this process. Histamine and ST-1006 down-regulated the expression of C3aR with different time kinetics on fully differentiated M2 macrophages. By analysing C3a-induced IL-6 mRNA expression, we observed a diminished response to C3a in ST-1006-treated M2 macrophages when compared to un-treated cells. Expression of C3 was not affected by histamine, whereas IL-4 strongly down-regulated C3aR and C3 expressions. Our data suggests that down-regulation of C3aR expression by mediators present in allergic situations such as IL-4 or histamine has an anti-inflammatory impact by reducing the sensitivity to C3a-induced down-stream signaling, thereby contributing to the regulation of local inflammatory responses in the skin.

scholarly journals β2-Adrenergic Receptor Enhances the Alternatively Activated Macrophages and Promotes Biliary Injuries Caused by Helminth Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Stephane Koda ◽  
Beibei Zhang ◽  
Qian-Yang Zhou ◽  
Na Xu ◽  
Jing Li ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Adrenergic Receptors ◽  
M2 Macrophages ◽  
Activated Macrophages ◽  
Alternatively Activated Macrophages ◽  
Mtorc1 Signaling ◽  
Β2 Adrenergic Receptor ◽  
Alternatively Activated

The autonomic nervous system has been studied for its involvement in the control of macrophages; however, the mechanisms underlying the interaction between the adrenergic receptors and alternatively activated macrophages (M2) remain obscure. Using FVB wild-type and beta 2 adrenergic receptors knockout, we found that β2-AR deficiency alleviates hepatobiliary damage in mice infected with C. sinensis. Moreover, β2-AR-deficient mice decrease the activation and infiltration of M2 macrophages and decrease the production of type 2 cytokines, which are associated with a significant decrease in liver fibrosis in infected mice. Our in vitro results on bone marrow–derived macrophages revealed that macrophages from Adrb2−/− mice significantly decrease M2 markers and the phosphorylation of ERK/mTORC1 induced by IL-4 compared to that observed in M2 macrophages from Adrb2+/+. This study provides a better understanding of the mechanisms by which the β2-AR enhances type 2 immune response through the ERK/mTORC1 signaling pathway in macrophages and their role in liver fibrosis.

scholarly journals Thioredoxin Peroxidase Secreted by Fasciola hepatica Induces the Alternative Activation of Macrophages

2005 ◽  
Vol 73 (1) ◽  
pp. 166-173 ◽  
Author(s):  
Sheila Donnelly ◽  
Sandra M. O'Neill ◽  
Mary Sekiya ◽  
Grace Mulcahy ◽  
John P. Dalton
Keyword(s):  
Fasciola Hepatica ◽  
Interleukin 10 ◽  
Alternative Activation ◽  
Parasitic Infections ◽  
Prostaglandin E ◽  
Th2 Response ◽  
Alternatively Activated Macrophages ◽  
Thioredoxin Peroxidase ◽  
Alternatively Activated

ABSTRACT Alternatively activated macrophages (AAMφ) are primarily associated with the chronic stages of parasitic infections and the development of a polarized Th2 response. We have shown that Fasciola hepatica infection of BALB/c mice induces a polarized Th2 response during both the latent and chronic stage of disease. The activation status of macrophages was analyzed in this model of helminth infection by evaluating the expression of genetic markers of alternative activation, namely, Fizz1, Ym1, and Arg1. AAMφ were recruited to the peritoneum of mice within 24 h of F. hepatica infection and after intraperitoneal injection of parasite excretory-secretory (ES) products. Administration of a recombinant antioxidant thioredoxin peroxidase (TPx), which is contained within the ES products, also induced the recruitment of AAMφ to the peritoneum. In vitro studies showed that this recombinant TPx directly converts RAW 264.7 macrophages to an alternatively activated phenotype characterized by the production of high levels of interleukin-10 (IL-10), prostaglandin E2, corresponding with low levels of IL-12. Our data suggest that the Th2 responses induced by the helminth F. hepatica are mediated through the secretion of molecules, one of which is TPx, that induce the recruitment and alternative activation of macrophages.

Naphthoquinones and derivatives for chemotherapy: perspectives and limitations of their anti-trypanosomatids activities

2020 ◽  
Vol 26 ◽  
Author(s):  
Luíza Dantas-Pereira ◽  
Edézio F. Cunha-Junior ◽  
Valter V. Andrade-Neto ◽  
John F. Bower ◽  
Guilherme A. M. Jardim ◽  
...  
Keyword(s):  
Large Scale ◽  
Neglected Tropical Diseases ◽  
Folk Medicine ◽  
Leishmania Species ◽  
Parasitic Infections ◽  
Mechanistic Analysis ◽  
Leishmania Spp ◽  
Nanomolar Range

: Chagas disease, Sleeping sickness and Leishmaniasis, caused by trypanosomatids Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., respectively, are considered neglected tropical diseases, and they especially affect impoverished populations in the developing world. The available chemotherapies are very limited and a search for alternatives is still necessary. In folk medicine, natural naphthoquinones have been employed for the treatment of a great variety of illnesses, including parasitic infections. This review is focused on the anti-trypanosomatid activity and mechanistic analysis of naphthoquinones and derivatives. Among all the series of derivatives tested in vitro, naphthoquinone-derived 1,2,3-triazoles were very active on T. cruzi infective forms in blood bank conditions, as well as in amastigotes of Leishmania spp. naphthoquinones containing a CF3 on a phenyl amine ring inhibited T. brucei proliferation in the nanomolar range, and naphthopterocarpanquinones stood out for their activity on a range of Leishmania species. Some of these compounds showed a promising selectivity index (SI) (30 to 1900), supporting further analysis in animal models. Indeed, high toxicity to the host and inactivation by blood components are crucial obstacles to be overcome to use naphthoquinones and/or their derivatives for chemotherapy. Multidisciplinary initiatives embracing medicinal chemistry, bioinformatics, biochemistry, and molecular and cellular biology need to be encouraged to allow the optimization of these compounds. Large scale automated tests are pivotal for the efficiency of the screening step, and subsequent evaluation of both the mechanism of action in vitro and pharmacokinetics in vivo are essential for the development of a novel, specific and safe derivative, minimizing adverse effects.

The impact of Zataria multiflora Boiss extract on in vitro and in vivo Th1/Th2 cytokine (IFN-γ/IL4) balance

2013 ◽  
Vol 150 (3) ◽  
pp. 1024-1031 ◽  
Author(s):  
Mohammad Hossein Boskabady ◽  
Sakine Shahmohammadi Mehrjardi ◽  
Abadorrahim Rezaee ◽  
Houshang Rafatpanah ◽  
Sediqeh Jalali
Keyword(s):  
Zataria Multiflora ◽  
Th2 Cytokine ◽  
Ifn Γ ◽  
The Impact

scholarly journals Regulation of Serum Exosomal MicroRNAs in Mice Infected with Orientia tsutsugamushi

2020 ◽  
Vol 9 (1) ◽  
pp. 80
Author(s):  
Le Jiang ◽  
Tatyana Belinskaya ◽  
Zhiwen Zhang ◽  
Teik-Chye Chan ◽  
Wei-Mei Ching ◽  
...  
Keyword(s):  
Post Infection ◽  
Viral Infections ◽  
Scrub Typhus ◽  
Late Phase ◽  
Many Body ◽  
Host Immune Responses ◽  
Lethal Infection ◽  
Exosomal Mirnas ◽  
Exosomal Mirna ◽  
Intercellular Communications

Exosomes are small extracellular vesicles that carry proteins, lipids, and nucleic acids. They are circulated in many body fluids and play an important role in intercellular communications. MicroRNAs (miRNAs), as major components of exosomes, are often regulated in many diseases including bacterial and viral infections. Functionally, exosome-carried miRNAs interact with various immune cells and affect their behavior. Little is known whether exosomal miRNAs are regulated during scrub typhus, a potentially lethal infection caused by intracellular bacteria, Orientiatsutsugamushi. In the present study, we utilized a scrub typhus mouse model and collected serum at various time points post infection. A custom quantitative PCR array covering 92 murine miRNAs was used to profile serum exosomal miRNAs. A total of 12 miRNAs were found to be significantly up- or down-regulated at least at one time point post infection when compared to uninfected animals. Further analysis identified multiple miRNAs in the let-7 family that were consistently down-regulated at early and late phase of infection. Functionally, serum exosomes isolated from infected mice displayed strong proinflammatory effect when incubated with bone marrow-derived macrophages. Our data revealed dynamic regulations of serum exosomal miRNA during scrub typhus infection, which could significantly influence host immune responses and disease outcome.

scholarly journals Antimalarial drugs—are they beneficial in rheumatic and viral diseases?—considerations in COVID-19 pandemic

2021 ◽  
Author(s):  
Bogna Grygiel-Górniak
Keyword(s):  
Connective Tissue ◽  
Viral Infections ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Antiviral Drugs ◽  
In Vivo Studies ◽  
Viral Diseases ◽  
Cardiac Complications

AbstractThe majority of the medical fraternity is continuously involved in finding new therapeutic schemes, including antimalarial medications (AMDs), which can be useful in combating the 2019-nCoV: coronavirus disease (COVID-19). For many decades, AMDs have been widely used in the treatment of malaria and various other anti-inflammatory diseases, particularly to treat autoimmune disorders of the connective tissue. The review comprises in vitro and in vivo studies, original studies, clinical trials, and consensus reports for the analysis, which were available in medical databases (e.g., PubMed). This manuscript summarizes the current knowledge about chloroquine (CQ)/hydroxychloroquine (HCQ) and shows the difference between their use, activity, recommendation, doses, and adverse effects on two groups of patients: those with rheumatic and viral diseases (including COVID-19). In the case of connective tissue disorders, AMDs are prescribed for a prolonged duration in small doses, and their effect is observed after few weeks, whereas in the case of viral infections, they are prescribed in larger doses for a short duration to achieve a quick saturation effect. In rheumatic diseases, AMDs are well tolerated, and their side effects are rare. However, in some viral diseases, the effect of AMDs is questionable or not so noticeable as suggested during the initial prognosis. They are mainly used as an additive therapy to antiviral drugs, but recent studies have shown that AMDs can diminish the efficacy of some antiviral drugs and may cause respiratory, kidney, liver, and cardiac complications.

scholarly journals Effect of Coxsackievirus B4 Infection on the Thymus: Elucidating Its Role in the Pathogenesis of Type 1 Diabetes

2021 ◽  
Vol 9 (6) ◽  
pp. 1177
Author(s):  
Abdulaziz Alhazmi ◽  
Magloire Pandoua Nekoua ◽  
Hélène Michaux ◽  
Famara Sane ◽  
Aymen Halouani ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Viral Infections ◽  
Lymphoid Organ ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Coxsackievirus B4

The thymus gland is a primary lymphoid organ for T-cell development. Various viral infections can result in disturbance of thymic functions. Medullary thymic epithelial cells (mTECs) are important for the negative selection of self-reactive T-cells to ensure central tolerance. Insulin-like growth factor 2 (IGF2) is the dominant self-peptide of the insulin family expressed in mTECs and plays a crucial role in the intra-thymic programing of central tolerance to insulin-secreting islet β-cells. Coxsackievirus B4 (CVB4) can infect and persist in the thymus of humans and mice, thus hampering the T-cell maturation and differentiation process. The modulation of IGF2 expression and protein synthesis during a CVB4 infection has been observed in vitro and in vivo in mouse models. The effect of CVB4 infections on human and mouse fetal thymus has been studied in vitro. Moreover, following the inoculation of CVB4 in pregnant mice, the thymic function in the fetus and offspring was disturbed. A defect in the intra-thymic expression of self-peptides by mTECs may be triggered by CVB4. The effects of viral infections, especially CVB4 infection, on thymic cells and functions and their possible role in the pathogenesis of type 1 diabetes (T1D) are presented.

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