scholarly journals Staphylococci planktonic and biofilm environments differentially affect macrophage immune activation and osteoclastogenic differentiation.

2021 ◽  
Author(s):  
Elisabeth Seebach ◽  
Tabea Elschner ◽  
Franziska V. Kraus ◽  
Margarida Souto-Carneiro ◽  
Katharina Kubatzky
Keyword(s):  
Immune Response ◽  
Immune Activation ◽  
Biofilm Formation ◽  
Cell Activation ◽  
Immune Cell ◽  
Bone Destruction ◽  
Osteoclast Formation ◽  
Bacterial Biofilm ◽  
Macrophage Response ◽  
Bone Infections

Implant-related bone infections are a major complication in orthopedic surgery that lead to inflammation and bone destruction. Bacterial biofilm formation on the implant is discussed to polarize the immune response towards tolerance and to facilitate bacterial persistence. In addition to their role in the early immune response, macrophages are osteoclast precursor cells. Therefore, macrophages can link inflammation and RANKL-mediated osteoclastogenic bone destruction. We investigated the influence of Staphylococcus aureus (SA) and epidermidis (SE) biofilm formation on immune function and osteoclastogenesis using RAW264.7 cells and conditioned media (CM) of planktonic and biofilm cultures in the presence and absence of the osteoclastogenic transcription factor RANKL. Analysis of immune cell activation, metabolic activity and osteoclast formation revealed that a planktonic environment causes a pro-inflammatory response. This was also partially induced by biofilm CM. Simultaneous stimulation with CM and RANKL suppressed osteoclast formation in favor of a long-term immune activation. While the early macrophage response towards CM was dominated by glycolysis, the CM and RANKL approach shifted metabolism towards increased mitochondrial biomass and activity. This was most evident in biofilm CM. We further showed that planktonic CM effects are mediated through activation of TLR signaling and induction of IFN-β production. In biofilm CM, high lactate levels seem to significantly contribute to the modulation of macrophages. Our results can contribute to find targets for therapeutic intervention that restore an effective pro-inflammatory immune response, which could help to control implant-related bone infections.

Abstract MP41: A Role Of Isolevuglandins In Systemic Lupus Erythematosus Associated Autoimmunity And Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
David M Patrick ◽  
Nestor de la Visitacion ◽  
Michelle J Ormseth ◽  
Charles Stein ◽  
Sean S Davies ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune Activation ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Immune Cell ◽  
Healthy Controls ◽  
Systemic Lupus ◽  
Immune Cell Activation ◽  
Systemic Immune Activation

Essential hypertension and systemic lupus erythematosus (SLE) are devastating conditions that disproportionately affect women. SLE has heterogeneous manifestations and treatment is limited to the use of non-specific global immunosuppression. Importantly, there is an increased prevalence of hypertension in women with SLE compared to healthy controls. Isolevuglandins (IsoLGs) are oxidation products of fatty acids that form as a result of reactive oxygen species. These molecules adduct covalently to lysine residues of proteins. Adducted proteins are then presented as autoantigens to T-cells resulting in immune cell activation. Previous studies have shown an essential role of IsoLGs in immune cell activation and the development of hypertension in animal models. We hypothesize that isoLGs are important for the development of hypertension and systemic immune activation in SLE. We first examined isoLG adduct accumulation within monocytes of human subjects with SLE compared to healthy controls. By flow cytometry, we found marked accumulation of isoLG adducts within CD14 + monocytes (34.2% ± 12.4% vs 3.81% ± 2.1% of CD14 + , N = 10-11, P <0.05). We confirmed this increase in isoLG adducts by mass spectrometry. To determine a causative role of isoLG adducts in immune activation and hypertension in SLE, we employed the B6.SLE123 and NZBWF1 mouse models of SLE. Animals were treated with the isoLG scavenger 2-hydroxybenzylamine (2-HOBA) or vehicle beginning at 7 weeks and were sacrificed at 32 weeks of age. C57BL/6 and NZW were used as controls. Importantly, treatment with 2-HOBA attenuated blood pressure in both mouse models (systolic BP 136.2 ± 5.6 mmHg for B6.SLE123 vs 120.9 ± 4.46 mmHg for B6.SLE123 +2HOBA; 164.7 ± 24.4 mmHg for NZBWF1 vs 136.9 ± 14.9 mmHg for NZBWF1 +2HOBA, N = 6-8, P < 0.05). Moreover, treatment with 2-HOBA reduced albuminuria and renal injury in the B6.SLE123 model (albumin/creatinine ratio 33.8 ± 2.0 x 10 -2 μg/mg for B6.SLE123 vs 5.5 ± 0.9 x 10 -2 μg/mg for B6.SLE123 +2HOBA, N = 7-9, P < 0.05). Finally, immune cell accumulation in primary and secondary lymphoid organs is significantly attenuated by 2-HOBA. These studies suggest a critical role of isoLG adduct accumulation in both systemic immune activation and hypertension in SLE.

scholarly journals Identification of distinct immune activation profiles in adult humans

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Renaud Cezar ◽  
Audrey Winter ◽  
Delphine Desigaud ◽  
Manuela Pastore ◽  
Lucy Kundura ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Nk Cell ◽  
Liver Steatosis ◽  
Treg Cells ◽  
Microbial Translocation ◽  
Color Flow

AbstractLatent infectious agents, microbial translocation, some metabolites and immune cell subpopulations, as well as senescence modulate the level and quality of activation of our immune system. Here, we tested whether various in vivo immune activation profiles may be distinguished in a general population. We measured 43 markers of immune activation by 8-color flow cytometry and ELISA in 150 adults, and performed a double hierarchical clustering of biomarkers and volunteers. We identified five different immune activation profiles. Profile 1 had a high proportion of naïve T cells. By contrast, Profiles 2 and 3 had an elevated percentage of terminally differentiated and of senescent CD4+ T cells and CD8+ T cells, respectively. The fourth profile was characterized by NK cell activation, and the last profile, Profile 5, by a high proportion of monocytes. In search for etiologic factors that could determine these profiles, we observed a high frequency of naïve Treg cells in Profile 1, contrasting with a tendency to a low percentage of Treg cells in Profiles 2 and 3. Moreover, Profile 5 tended to have a high level of 16s ribosomal DNA, a direct marker of microbial translocation. These data are compatible with a model in which specific causes, as the frequency of Treg or the level of microbial translocation, shape specific profiles of immune activation. It will be of interest to analyze whether some of these profiles drive preferentially some morbidities known to be fueled by immune activation, as insulin resistance, atherothrombosis or liver steatosis.

scholarly journals The Carbohydrate Lectin Receptor Dectin-1 Mediates the Immune Response to Exserohilum rostratum

2016 ◽  
Vol 85 (3) ◽  
Author(s):  
Jennifer L. Reedy ◽  
Paige E. Negoro ◽  
Marianela Feliu ◽  
Allison K. Lord ◽  
Nida S. Khan ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cell ◽  
Wide Spectrum ◽  
Granulomatous Inflammation ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Macrophage Response ◽  
Lectin Receptor ◽  
Exserohilum Rostratum

ABSTRACT Dematiaceous molds are found ubiquitously in the environment and cause a wide spectrum of human disease, including infections associated with high rates of mortality. Despite this, the mechanism of the innate immune response has been less well studied, although it is key in the clearance of fungal pathogens. Here, we focus on Exserohilum rostratum, a dematiaceous mold that caused 753 infections during a multistate outbreak due to injection of contaminated methylprednisolone. We show that macrophages are incapable of phagocytosing Exserohilum. Despite a lack of phagocytosis, macrophage production of tumor necrosis factor alpha is triggered by hyphae but not spores and depends upon Dectin-1, a C-type lectin receptor. Dectin-1 is specifically recruited to the macrophage-hyphal interface but not the macrophage-spore interface due to differences in carbohydrate antigen expression between these two fungal forms. Corticosteroid and antifungal therapy perturb this response, resulting in decreased cytokine production. In vivo soft tissue infection in wild-type mice demonstrated that Exserohilum provokes robust neutrophilic and granulomatous inflammation capable of thwarting fungal growth. However, coadministration of methylprednisolone acetate results in robust hyphal tissue invasion and a significant reduction in immune cell recruitment. Our results suggest that Dectin-1 is crucial for macrophage recognition and the macrophage response to Exserohilum and that corticosteroids potently attenuate the immune response to this pathogen.

scholarly journals Antibiotics Differentially Modulate Lipoteichoic Acid-Mediated Host Immune Response

Antibiotics ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 573
Author(s):  
Marquerita Algorri ◽  
Annie Wong-Beringer
Keyword(s):  
Immune Response ◽  
Cell Surface ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Ex Vivo ◽  
Human Peripheral Blood ◽  
Lipoteichoic Acid ◽  
Cytokine Response ◽  
Hla Dr

In Staphylococcus aureus bacteremia, our group has shown that a dysregulated balance of pro- and anti-inflammatory cytokine response biased towards an immunoparalysis phenotype is predictive of persistence and mortality, despite receipt of antibiotics. Certain antibiotics, as well as lipoteichoic acid (LTA) released from S. aureus, can modulate immune response ex vivo. Here, we evaluated the effects of three anti-staphylococcal antibiotics (vancomycin, tedizolid, and daptomycin) on the expression of cytokines and cell surface markers of immune activation (TNFα, HLA-DR) and immunoparalysis (IL-10, PD-L1) in human peripheral blood mononuclear cells (PBMC) exposed to high (10 μg) and low (1 μg) doses of LTA. Results suggested a dose-dependent relationship between LTA and induction of anti- and pro-inflammatory immune responses. Differential antibiotic effects were prominently observed at high but not low LTA condition. Vancomycin significantly induced IL-10 and TNFα expression, whereas daptomycin had no effects on cytokine response or expression of cell surface receptors. Tedizolid increased TNFα and modestly increased HLA-DR expression, suggesting a stimulatory effect. These findings suggest that anti-staphylococcal agents differentially alter LTA-mediated immune cell activation status and cytokine response, providing support for future clinical studies to better elucidate the complexities of host–microbial–antibiotic interaction that can help direct precision therapy for S. aureus bacteremia.

scholarly journals 254 NTX-1088, a potent anti-PVR Mab induces DNAM1-mediated antitumor immunity

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A275-A275
Author(s):  
Anas Atieh ◽  
Akram Obiedat ◽  
Guy Cinamon ◽  
Tihana Lenac Rovis ◽  
Paola Kucan Brlic ◽  
...  
Keyword(s):  
T Cells ◽  
Synergistic Effect ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Immune Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Tumor Growth Inhibition

BackgroundPoliovirus receptor (PVR, CD155) represents a resistance mechanism to approved immune checkpoint inhibitors (ICIs). It is a key regulator of immune activation, that modifies function through multiple mechanisms. Increased PVR expression levels on tumor cells have been associated with resistance to anti-PD-(L)1 therapy, while loss of PVR led to reduced tumor growth. Targeting PVR using mAbs offers an attractive therapeutic approach for patients with advanced cancer, who are not responding to other ICIs.NTX-1088 is a first-in-class, anti-PVR mAb developed for the treatment of solid tumors and will enter clinical trials early 2022. The antibody binds PVR with high affinity, blocks its interactions with TIGIT and CD96, preventing their inhibitory signaling. Moreover, NTX-1088 forte is manifested through its ability to block the critical interaction between PVR and DNAM1 (CD226). This blockade prevents internalization of DNAM1, restores its expression on the surface of immune cells and results in a robust antitumor activity.MethodsNTX-1088 was rigorously tested in vitro and in-vivo. Various cancer cell lines were incubated with immune effector cells from healthy human donors, in the presence of NTX-1088, alone and in combination with anti-PD-1 mAb (pembrolizumab).ResultsNTX-1088 significantly increased immune cell activation, as measured by IFNg release from activated polyclonal CD8+ T cells, induction of CD137 and killing of tumor cells. When tested in combination with pembrolizumab, NTX-1088 further increased all measured activation parameters, suggesting a potential synergistic effect. A synergistic effect was obtained when NTX-1088 was combined with the anti-CD112R mAb, NTX-2R13, superior to TIGIT-CD112R combinations. When compared to anti-TIGIT mAb (tiragolumab), NTX-1088 demonstrated clear superiority in activating T and NK cells as stand-alone agent. Furthermore NTX-1088 in combination with pembrolizumab, was superior to the combination of pembrolizumab with anti-TIGIT.Importantly, NTX-1088 was the only intervention that significantly restored DNAM1 levels, whereas DNAM1 blockade reduced the activity of NTX-1088 to levels comparable to that of anti-TIGIT mAb.Humanized murine models confirmed the above observations; NTX-1088 exhibited a robust tumor growth inhibition, accompanied by significantly higher prevalence of CD137+, DNAM1+, CD8+ T cells, compared to mice treated by other ICIs.ConclusionsThis is the first report of drug-induced DNAM1 restoration and immune activation. NTX-1088 shows, for the first time, exclusive triple mechanism of action, whereby simultaneous and effective blockade of TIGIT and CD96 is complemented by the efficient restoration of DNAM1. This is a step change in antitumor immune activation, which will be validated in the clinic starting early 2022.

scholarly journals Vaccines against Human Carcinomas: Strategies to Improve Antitumor Immune Responses

2010 ◽  
Vol 2010 ◽  
pp. 1-12 ◽  
Author(s):  
Claudia Palena ◽  
Jeffrey Schlom
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Tumor Growth ◽  
Cancer Vaccines ◽  
Cell Activation ◽  
Immune Cell ◽  
Immune Escape ◽  
Adaptive Immune Response ◽  
Tumor Immune Escape ◽  
Multiple Observations

Multiple observations in preclinical and clinical studies support a role for the immune system in controlling tumor growth and progression. Various components of the innate and adaptive immune response are able to mediate tumor cell destruction; however, certain immune cell populations can also induce a protumor environment that favors tumor growth and the development of metastasis. Moreover, tumor cells themselves are equipped with various mechanisms that allow them to evade surveillance by the immune system. The goal of cancer vaccines is to induce a tumor-specific immune response that ultimately will reduce tumor burden by tipping the balance from a protumor to an antitumor immune environment. This review discusses common mechanisms that govern immune cell activation and tumor immune escape, and some of the current strategies employed in the field of cancer vaccines aimed at enhancing activation of tumor-specific T-cells with concurrent reduction of immunosuppression.

scholarly journals N6-Methyladenosine in Cancer Immunotherapy: An Undervalued Therapeutic Target

2021 ◽  
Vol 12 ◽  
Author(s):  
Chao Quan ◽  
Othmane Belaydi ◽  
Jiao Hu ◽  
Huihuang Li ◽  
Anze Yu ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Activation ◽  
Immune Cell ◽  
Immune Cell Activation ◽  
Nucleotide Modification ◽  
Transcriptional Regulatory Mechanism ◽  
Transcriptional Regulatory ◽  
Almost All ◽  
Tumor Types

N6-methylation of adenosine (m6A), a post-transcriptional regulatory mechanism, is the most abundant nucleotide modification in almost all types of RNAs. The biological function of m6A in regulating the expression of oncogenes or tumor suppressor genes has been widely investigated in various cancers. However, recent studies have addressed a new role of m6A modification in the anti-tumor immune response. By modulating the fate of targeted RNA, m6A affects tumor-associated immune cell activation and infiltration in the tumor microenvironment (TME). In addition, m6A-targeting is found to affect the efficacy of classical immunotherapy, which makes m6A a potential target for immunotherapy. Although m6A modification together with its regulators may play the exact opposite role in different tumor types, targeting m6A regulators has been shown to have wide implications in several cancers. In this review, we discussed the link between m6A modification and tumor with an emphasis on the importance of m6A in anti-tumor immune response and immunotherapy.

scholarly journals Key Macrophage Responses to Infection With Mycobacterium tuberculosis Are Co-Regulated by microRNAs and DNA Methylation

2021 ◽  
Vol 12 ◽  
Author(s):  
Monika Looney ◽  
Rachel Lorenc ◽  
Marc K. Halushka ◽  
Petros C. Karakousis
Keyword(s):  
Dna Methylation ◽  
Mycobacterium Tuberculosis ◽  
Cell Activation ◽  
Immune Cell ◽  
Methylation Status ◽  
Bacterial Pathogen ◽  
Macrophage Infection ◽  
Macrophage Response ◽  
Human Macrophages

Tuberculosis (TB) is the leading cause of death from infection with a single bacterial pathogen. Host macrophages are the primary cell type infected with Mycobacterium tuberculosis (Mtb), the organism that causes TB. Macrophage response pathways are regulated by various factors, including microRNAs (miRNAs) and epigenetic changes that can shape the outcome of infection. Although dysregulation of both miRNAs and DNA methylation have been studied in the context of Mtb infection, studies have not yet investigated how these two processes may jointly co-regulate critical anti-TB pathways in primary human macrophages. In the current study, we integrated genome-wide analyses of miRNA abundance and DNA methylation status with mRNA transcriptomics in Mtb-infected primary human macrophages to decipher which macrophage functions may be subject to control by these two types of regulation. Using in vitro macrophage infection models and next generation sequencing, we found that miRNAs and methylation changes co-regulate important macrophage response processes, including immune cell activation, macrophage metabolism, and AMPK pathway signaling.

scholarly journals Transposable elements have contributed human regulatory regions that are activated upon bacterial infection

2020 ◽  
Vol 375 (1795) ◽  
pp. 20190332 ◽  
Author(s):  
Lucia Bogdan ◽  
Luis Barreiro ◽  
Guillaume Bourque
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Transposable Elements ◽  
Cell Activation ◽  
Immune Cell ◽  
Regulation Of Gene Expression ◽  
Interferon Response ◽  
Human Interferon ◽  
Trait Locus ◽  
Accessible Chromatin

Transposable elements (TEs) are increasingly recognized as important contributors to mammalian regulatory systems. For instance, they have been shown to play a role in the human interferon response, but their involvement in other mechanisms of immune cell activation remains poorly understood. Here, we investigated the profile of accessible chromatin enhanced in stimulated human macrophages using ATAC-seq to assess the role of different TE subfamilies in regulating gene expression following an immune response. We found that both previously identified and new repeats belonging to the MER44, THE1, Tigger3 and MLT1 families provide 14 subfamilies that are enriched in differentially accessible chromatin and found near differentially expressed genes. These TEs also harbour binding motifs for several candidate transcription factors, including important immune regulators AP-1 and NF-κB, present in 96% of accessible MER44B and 83% of THE1C instances, respectively. To more directly assess their regulatory potential, we evaluated the presence of these TEs in regions putatively affecting gene expression, as defined by quantitative trait locus (QTL) analysis, and found that repeats are also contributing to accessible elements near QTLs. Together, these results suggest that a number of TE families have contributed to the regulation of gene expression in the context of the immune response to infection in humans. This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.

scholarly journals Mechanisms of Bone Resorption in Periodontitis

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Stefan A. Hienz ◽  
Sweta Paliwal ◽  
Saso Ivanovski
Keyword(s):  
Immune Response ◽  
Bone Loss ◽  
Alveolar Bone ◽  
Immune Cell ◽  
Periodontal Diseases ◽  
Adaptive Immune Response ◽  
Bone Destruction ◽  
Proinflammatory Mediators ◽  
Expression Pathways ◽  
Macrophage Colony

Alveolar bone loss is a hallmark of periodontitis progression and its prevention is a key clinical challenge in periodontal disease treatment. Bone destruction is mediated by the host immune and inflammatory response to the microbial challenge. However, the mechanisms by which the local immune response against periodontopathic bacteria disturbs the homeostatic balance of bone formation and resorption in favour of bone loss remain to be established. The osteoclast, the principal bone resorptive cell, differentiates from monocyte/macrophage precursors under the regulation of the critical cytokines macrophage colony-stimulating factor, RANK ligand, and osteoprotegerin. TNF-α, IL-1, and PGE2also promote osteoclast activity, particularly in states of inflammatory osteolysis such as those found in periodontitis. The pathogenic processes of destructive inflammatory periodontal diseases are instigated by subgingival plaque microflora and factors such as lipopolysaccharides derived from specific pathogens. These are propagated by host inflammatory and immune cell influences, and the activation of T and B cells initiates the adaptive immune response via regulation of the Th1-Th2-Th17 regulatory axis. In summary, Th1-type T lymphocytes, B cell macrophages, and neutrophils promote bone loss through upregulated production of proinflammatory mediators and activation of the RANK-L expression pathways.

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