scholarly journals Protein PGLYRP1/Tag7 Peptides Decrease the Proinflammatory Response in Human Blood Cells and Mouse Model of Diffuse Alveolar Damage of Lung through Blockage of the TREM-1 and TNFR1 Receptors

2021 ◽  
Vol 22 (20) ◽  
pp. 11213
Author(s):  
Tatiana N. Sharapova ◽  
Elena A. Romanova ◽  
Aleksandr S. Chernov ◽  
Alexey N. Minakov ◽  
Vitaly A. Kazakov ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mouse Model ◽  
Proinflammatory Cytokines ◽  
Mononuclear Cells ◽  
Diffuse Alveolar Damage ◽  
Proinflammatory Response ◽  
Peripheral Blood Mononuclear ◽  
Terminal Fragment

Infection caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) in many cases is accompanied by the release of a large amount of proinflammatory cytokines in an event known as “cytokine storm”, which is associated with severe coronavirus disease 2019 (COVID-19) cases and high mortality. The excessive production of proinflammatory cytokines is linked, inter alia, to the enhanced activity of receptors capable of recognizing the conservative regions of pathogens and cell debris, namely TLRs, TREM-1 and TNFR1. Here we report that peptides derived from innate immunity protein Tag7 inhibit activation of TREM-1 and TNFR1 receptors during acute inflammation. Peptides from the N-terminal fragment of Tag7 bind only to TREM-1, while peptides from the C-terminal fragment interact solely with TNFR1. Selected peptides are capable of inhibiting the production of proinflammatory cytokines both in peripheral blood mononuclear cells (PBMCs) from healthy donors and in vivo in the mouse model of acute lung injury (ALI) by diffuse alveolar damage (DAD). Treatment with peptides significantly decreases the infiltration of mononuclear cells to lungs in animals with DAD. Our findings suggest that Tag7-derived peptides might be beneficial in terms of the therapy or prevention of acute lung injury, e.g., for treating COVID-19 patients with severe pulmonary lesions.

scholarly journals Establishment of a Novel Humanized Mouse Model To Investigate In Vivo Activation and Depletion of Patient-Derived HIV Latent Reservoirs

2019 ◽  
Vol 93 (6) ◽  
Author(s):  
Nina C. Flerin ◽  
Ariola Bardhi ◽  
Jian Hua Zheng ◽  
Maria Korom ◽  
Joy Folkvord ◽  
...  
Keyword(s):  
Mouse Model ◽  
Hiv Infection ◽  
Mononuclear Cells ◽  
Systemic Infection ◽  
Humanized Mouse Model ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficient Mice ◽  
Latently Infected ◽  
Infected Cells

ABSTRACT Curing HIV infection has been thwarted by the persistent reservoir of latently infected CD4+ T cells, which reinitiate systemic infection after antiretroviral therapy (ART) interruption. To evaluate reservoir depletion strategies, we developed a novel preclinical in vivo model consisting of immunodeficient mice intrasplenically injected with peripheral blood mononuclear cells (PBMC) from long-term ART-suppressed HIV-infected donors. In the absence of ART, these mice developed rebound viremia which, 2 weeks after PBMC injection, was 1,000-fold higher (mean = 9,229,281 HIV copies/ml) in mice injected intrasplenically than in mice injected intraperitoneally (mean = 6,838 HIV copies/ml) or intravenously (mean = 591 HIV copies/ml). One week after intrasplenic PBMC injection, in situ hybridization of the spleen demonstrated extensive disseminated HIV infection, likely initiated from in vivo-reactivated primary latently infected cells. The time to viremia was delayed significantly by treatment with a broadly neutralizing antibody, 10-1074, compared to treatment with 10-1074-FcRnull, suggesting that 10-1074 mobilized Fc-mediated effector mechanisms to deplete the replication-competent reservoir. This was supported by phylogenetic analysis of Env sequences from viral-outgrowth cultures and untreated, 10-1074-treated, or 10-1074-FcRnull-treated mice. The predominant sequence cluster detected in viral-outgrowth cultures and untreated mouse plasma was significantly reduced in the plasma of 10-1074-treated mice, whereas two new clusters emerged that were not detected in viral-outgrowth cultures or plasma from untreated mice. These new clusters lacked mutations associated with 10-1074 resistance. Taken together, these data indicated that 10-1074 treatment depletes the reservoir of latently infected cells harboring replication competent HIV. Furthermore, this mouse model represents a new in vivo approach for the preclinical evaluation of new HIV cure strategies. IMPORTANCE Sustained remission of HIV infection is prevented by a persistent reservoir of latently infected cells capable of reinitiating systemic infection and viremia. To evaluate strategies to reactivate and deplete this reservoir, we developed and characterized a new humanized mouse model consisting of highly immunodeficient mice intrasplenically injected with peripheral blood mononuclear cells from long-term ART-suppressed HIV-infected donors. Reactivation and dissemination of HIV infection was visualized in the mouse spleens in parallel with the onset of viremia. The applicability of this model for evaluating reservoir depletion treatments was demonstrated by establishing, through delayed time to viremia and phylogenetic analysis of plasma virus, that treatment of these humanized mice with a broadly neutralizing antibody, 10-1074, depleted the patient-derived population of latently infected cells. This mouse model represents a new in vivo approach for the preclinical evaluation of new HIV cure strategies.

scholarly journals Fibrocytes Ameliorate Acute Lung Injury by Decreasing Inflammatory Cytokine and Chemokine Levels and Reducing Neutrophil Accumulation in the Lung

2017 ◽  
Vol 44 (4) ◽  
pp. 1526-1536 ◽  
Author(s):  
Wenlin Tai ◽  
Yiheng Xu ◽  
Jiawei Ding ◽  
Hanxin Wu ◽  
Ming Du ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mononuclear Cells ◽  
Human Life ◽  
Severe Disease ◽  
Lavage Fluid ◽  
Neutrophil Accumulation ◽  
Peripheral Blood Mononuclear ◽  
Tnf Α ◽  
Ifn Γ

Background/Aims: Acute lung injury (ALI) remains a severe disease that threatens human life around the world. To decrease the mortality of ALI and improve ALI treatment efficacy, the development of more ALI treatments is urgently needed. Whether fibrocytes directly participate in ALI has not been studied. Therefore, a mouse model of ALI was induced with lipopolysaccharide (LPS). Methods: Fibrocytes were harvested from peripheral blood mononuclear cells of bleomycin mice and identified by using flow cytometry to detect the expression of molecular makers. The fibrocytes were injected for the treatment of acute lung injury mice. The curative effects were evaluated by using ELISA to determine the cytokines (including TNF-α, IL-6 and IFN-γ) concentrations in bronchoalveolar lavage fluid (BALF) supernatant. Results: The concentrations of cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-γ (IFN-γ) were increased in mice with ALI induced with LPS. The concentrations of TNF-α, IL-6, and IFN-γ as well as their mRNA and protein expression levels were decreased by administration of fibrocytes. The effect of fibrocytes in ameliorating ALI was time dependent. LPS treatment induced an increase in myeloperoxidase (MPO) activity, whereas the fibrocyte treatment caused inhibition of MPO activity as well as expression of the neutrophil-chemoattractant chemokine macrophage inflammatory protein 2 (MIP-2). Conclusion: Taken together, these data suggest that fibrocytes ameliorated ALI by suppressing inflammatory cytokines and chemokines as well as by decreasing the accumulation of neutrophils in the lung.

scholarly journals Spermine Inhibits Proinflammatory Cytokine Synthesis in Human Mononuclear Cells: A Counterregulatory Mechanism that Restrains the Immune Response

1997 ◽  
Vol 185 (10) ◽  
pp. 1759-1768 ◽  
Author(s):  
Minghuang Zhang ◽  
Theresa Caragine ◽  
Haichao Wang ◽  
Pamela S. Cohen ◽  
Galina Botchkina ◽  
...  
Keyword(s):  
Immune Response ◽  
Proinflammatory Cytokines ◽  
Proinflammatory Cytokine ◽  
Mononuclear Cells ◽  
Molecular Mimicry ◽  
Human Peripheral Blood ◽  
Interleukin 1 ◽  
Peripheral Blood Mononuclear ◽  
Cytokine Synthesis

The local production of proinflammatory cytokines mediates the host response to inflammation, infection, and injury, whereas an overexpression of these mediators can injure or kill the host. Recently, we identified a class of multivalent guanylhydrazone compounds that are effective inhibitors of proinflammatory cytokine synthesis in monocytes/macrophages. The structure of one such cationic molecule suggested a molecular mimicry with spermine, a ubiquitous endogenous biogenic amine that increases significantly at sites of inflammation and infection. Here, we addressed the hypothesis that spermine might counterregulate the innate immune response by downregulating the synthesis of potentially injurious cytokines. When spermine was added to cultures of human peripheral blood mononuclear cells stimulated with lipopolysaccharide (LPS), it effectively inhibited the synthesis of the proinflammatory cytokines tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6, MIP-1α, and MIP-1β. The inhibition of cytokine synthesis was specific and reversible, with significant inhibition of TNF synthesis occurring even when spermine was added after LPS. The mechanism of spermine-mediated cytokine suppression was posttranscriptional and independent of polyamine oxidase activity. Local administration of spermine in vivo protected mice against the development of acute footpad inflammation induced by carrageenan. These results identify a distinct molecular counterregulatory role for spermine in downregulating the monocyte proinflammatory cytokine response.

scholarly journals A Novel cDNA-uPA/SCID/Rag2-/-/Jak3-/- Mouse Model for Hepatitis Virus Infection and Reconstruction of Human Immune System

2021 ◽  
Author(s):  
Takuro Uchida ◽  
Yuji Teraoka ◽  
Michio Imamura ◽  
Hatsue Fujino ◽  
Atsushi Ono ◽  
...  
Keyword(s):  
Immune System ◽  
Mouse Model ◽  
Mononuclear Cells ◽  
Hepatitis Virus ◽  
Human Leukocyte ◽  
Human Hepatocytes ◽  
Human Immune System ◽  
Peripheral Blood Mononuclear ◽  
Type Plasminogen Activator

Abstract The humanized mouse is a widely used in vivo model for the investigation of pathogenesis and drug development. In this study, we generated new immunodeficiency cDNA-urokinase-type plasminogen activator (uPA)/SCID/Rag2-/-/Jak3-/- mice and established the mouse model with a humanized liver and immune system. Transplantation of human hepatocytes with human leukocyte antigen (HLA)-A24 resulted in establishment of a highly replaced liver in this mouse model. These mice were successfully infected with hepatitis B virus and hepatis C virus (HCV) for a prolonged period and are available for the analysis of the effect of anti-HCV drugs. Administration of peripheral blood mononuclear cells (PBMCs) obtained from a donor with HLA-A24 resulted in the establishment of 22.6–81.3% of human CD45-positive mononuclear cell chimerism in liver infiltrating cells without causing graft versus host disease. When mice were transplanted with human hepatocytes and then administered PBMCs, an alloimmune response between transplanted human hepatocytes and PBMCs occurred, with production of transplanted hepatocyte-specific anti-HLA antibody. The alloimmunity was never inhibited by methylprednisolone nor cyclosporine A. In conclusion, we succeeded in establishing a humanized liver and immune system using a novel cDNA-uPA/SCID/Rag2-/-/Jak3-/- mouse. This model is not only useful to study hepatitis virus virology but also to study alloimmunity.

scholarly journals Phosphodiesterase-4 Inhibition Reduces Cutaneous Inflammation and IL-1β Expression in a Psoriasiform Mouse Model but Does Not Inhibit Inflammasome Activation

2021 ◽  
Vol 22 (23) ◽  
pp. 12878
Author(s):  
Barbara Meier-Schiesser ◽  
Mark Mellett ◽  
Marigdalia K. Ramirez-Fort ◽  
Julia-Tatjana Maul ◽  
Annika Klug ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mice ◽  
Proinflammatory Cytokines ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Pde4 Inhibitor ◽  
Inflammasome Activation ◽  
Phosphodiesterase 4 ◽  
Oral Ulcers

Apremilast (Otezla®) is an oral small molecule phosphodiesterase 4 (PDE4) inhibitor approved for the treatment of psoriasis, psoriatic arthritis, and oral ulcers associated with Behçet’s disease. While PDE4 inhibition overall is mechanistically understood, the effect of apremilast on the innate immune response, particularly inflammasome activation, remains unknown. Here, we assessed the effect of apremilast in a psoriasis mouse model and primary human cells. Psoriatic lesion development in vivo was studied in K5.Stat3C transgenic mice treated with apremilast for 2 weeks, resulting in a moderate (2 mg/kg/day) to significant (6 mg/kg/day) resolution of inflamed plaques after 2-week treatment. Concomitantly, epidermal thickness dramatically decreased, the cutaneous immune cell infiltrate was reduced, and proinflammatory cytokines were significantly downregulated. Additionally, apremilast significantly inhibited lipopolysaccharide- or anti-CD3-induced expression of proinflammatory cytokines in peripheral mononuclear cells (PBMCs). Notably, inflammasome activation and secretion of IL-1β were not inhibited by apremilast in PBMCs and in human primary keratinocytes. Collectively, apremilast effectively alleviated the psoriatic phenotype of K5.Stat3 transgenic mice, further substantiating PDE4 inhibitor-efficiency in targeting key clinical, histopathological and inflammatory features of psoriasis. Despite lacking direct effect on inflammasome activation, reduced priming of inflammasome components upon apremilast treatment reflected the indirect benefit of PDE4 inhibition in reducing inflammation.

scholarly journals Protective effect of suppressing STAT3 activity in LPS-induced acute lung injury

2016 ◽  
Vol 311 (5) ◽  
pp. L868-L880 ◽  
Author(s):  
Jiping Zhao ◽  
Hao Yu ◽  
Yudong Liu ◽  
Sara A. Gibson ◽  
Zhaoqi Yan ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mhc Class Ii ◽  
Mononuclear Cells ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Human Peripheral Blood ◽  
Peripheral Blood Mononuclear ◽  
Proinflammatory Mediators ◽  
Stat3 Phosphorylation

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are diseases with high mortality. Macrophages and neutrophils are responsible for inflammatory responses in ALI and ARDS, which are characterized by excessive production of proinflammatory mediators in bronchoalveolar lavage fluid (BALF) and plasma. Aberrant activation of the JAK/STAT pathway is critical for persistent inflammation in many conditions such as infection and autoimmunity. Given the importance of the STAT3 transcription factor in activating macrophages and neutrophils and augmenting inflammation, we investigated the therapeutic potential of inhibiting STAT3 activity using the small-molecule STAT3 inhibitor, LLL12. Our results demonstrate that LPS induces STAT3 activation in macrophages in vitro and in CD45+CD11b+ cells from BALF in the LPS-induced ALI model in vivo. LLL12 treatment inhibits LPS-induced lung inflammation in the ALI model, which is accompanied by suppression of LPS-induced STAT3 activation and an inhibition of macrophage and inflammatory cell infiltration in lung and BALF. LLL12 treatment also suppresses expression of proinflammatory genes including IL-1β, IL-6, TNF-α, iNOS, CCL2, and MHC class II in macrophages and inflammatory cells from BALF and serum as determined by ELISA. Furthermore, hyperactivation of STAT3 in LysMCre-SOCS3fl/fl mice accelerates the severity of inflammation in the ALI model. Both pre- and post-LPS treatment with LLL12 decrease LPS-induced inflammatory responses in mice with ALI. Importantly, LLL12 treatment attenuates STAT3 phosphorylation in human peripheral blood mononuclear cells induced by plasma from patients with ARDS, which suggests the feasibility of targeting the STAT3 pathway therapeutically for patients with ALI and ARDS.

scholarly journals Progranulin Improves Acute Lung Injury through Regulating the Differentiation of Regulatory T Cells and Interleukin-10 Immunomodulation to Promote Macrophage Polarization

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Yan-qing Chen ◽  
Chuan-jiang Wang ◽  
Ke Xie ◽  
Ming Lei ◽  
Yu-sen Chai ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lung Injury ◽  
Regulatory T Cells ◽  
Lung Injury ◽  
Mononuclear Cells ◽  
Macrophage Polarization ◽  
Inflammatory Factor ◽  
Peripheral Blood Mononuclear ◽  
Anti Inflammatory ◽  
Treg Differentiation

Progranulin (PGRN), which plays an anti-inflammatory role in acute lung injury (ALI), is promising as a potential drug. Studies have shown that regulatory T cells (Tregs) and interleukin- (IL-) 10 can repress inflammation and alleviate tissue damage during ALI. In this study, we built a lipopolysaccharide- (LPS-) induced ALI mouse model to illustrate the effect of PGRN on regulation of Treg differentiation and modulation of IL-10 promoting macrophage polarization. We found that the proportion of Tregs in splenic mononuclear cells and peripheral blood mononuclear cells was higher after treatment with PGRN. The increased proportion of Tregs after PGRN intratracheal instillation was consistent with the decreased severity of lung injury, the reduction of proinflammatory cytokines, and the increase of anti-inflammatory cytokines. In vitro, the percentages of CD4+CD25+FOXP3+ Tregs from splenic naïve CD4+ T cells increased after PGRN treatment. In further research, it was found that PGRN can regulate the anti-inflammatory factor IL-10 and affect the polarization of M1/M2 macrophages by upregulating IL-10. These findings show that PGRN likely plays a protective role in ALI by promoting Treg differentiation and activating IL-10 immunomodulation.

scholarly journals Overexpression of MALAT1 Relates to Lung Injury through Sponging miR-425 and Promoting Cell Apoptosis during ARDS

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Lu Wang ◽  
Jiao Liu ◽  
Wenjie Xie ◽  
Guang Li ◽  
Lan Yao ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Cell Apoptosis ◽  
Noncoding Rna ◽  
Mononuclear Cells ◽  
Inflammatory Responses ◽  
Severe Form ◽  
Luciferase Assay ◽  
Peripheral Blood Mononuclear ◽  
Tensin Homolog

Background. Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury during which severe inflammatory responses induce cell apoptosis, necrosis, and fibrosis. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a multiple function long noncoding RNA that was found overexpressed during acute lung injury. However, the roles of MALAT1 in ARDS patients are still unknown. Methods. Total RNA was extracted from the plasma, plasma exosome, and peripheral blood mononuclear cells (PBMCs) from 65 ARDS patients and 36 healthy controls. The MALAT1 and six candidate miRNAs levels were detected by qRT-PCR. The interaction between MALAT1 and miR-425 was predicted using a bioinformatics tool and verified by dual luciferase assay. Exosomes from ARDS patients were cultured with A549 and HFL-1 cells to confirm the delivery of miR-425 by exosomes. Cell apoptosis and viability were determined by flow cytometry and MTT assay. Results. We found MALAT1 was significantly increased in the ARDS patients’ plasma and PBMCs. The MALAT1 level in PBMCs was negatively correlated with exosomal miR-425 level. MALAT1 interacted with miR-425 and protected phosphatase and tensin homolog (PTEN) expression in A549 and HFL-1 cells. Exosomes from ARDS patients delivered less miR-425 into A549 and HFL-1 cells and induced cell apoptosis via upregulating PTEN. Conclusion. This study identified increased MALAT1 and decreased miR-425 in ARDS patients and unveiled their roles during the pathogenesis of ARDS.

scholarly journals Alpinumisoflavone attenuates lipopolysaccharide-induced acute lung injury by regulating the effects of anti-oxidation and anti-inflammation both in vitro and in vivo

RSC Advances ◽  
2018 ◽  
Vol 8 (55) ◽  
pp. 31515-31528 ◽  
Author(s):  
Pei-Ying Li ◽  
Yu-Chia Liang ◽  
Ming-Jyh Sheu ◽  
Shyh-Shyun Huang ◽  
Che-Yi Chao ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mouse Model ◽  
Raw264.7 Macrophages ◽  
Anti Inflammatory ◽  
Anti Inflammation

The present study demonstrated that alpinumisoflavone exerts the significant effects of anti-inflammatory and anti-oxidative in both LPS-induced RAW264.7 macrophages and a mouse model of acute lung injury.

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