scholarly journals LPS Induces Opposing Memory-like Inflammatory Responses in Mouse Bone Marrow Neutrophils

2021 ◽  
Vol 22 (18) ◽  
pp. 9803
Author(s):  
Trim Lajqi ◽  
Maylis Braun ◽  
Simon Alexander Kranig ◽  
David Frommhold ◽  
Johannes Pöschl ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
In Vivo Studies ◽  
Mouse Bone Marrow ◽  
Innate Immune Cells ◽  
Trained Immunity

A growing body of evidence suggests that innate immune cells can respond in a memory-like (adaptive) fashion, which is referred to as trained immunity. Only few in vivo studies have shown training effects in neutrophils; however, no in vitro setup has been established to study the induction of trained immunity or tolerance in neutrophils by microbial agents. In light of their short lifespan (up to 48 h), we suggest to use the term trained sensitivity for neutrophils in an in vitro setting. Here, we firstly describe a feasible two-hit model, using different doses of lipopolysaccharide (LPS) in bone marrow neutrophils. We found that low doses (10 pg/mL) induce pro-inflammatory activation (trained sensitivity), whereas priming with high doses (100 ng/mL) leads to suppression of pro-inflammatory mediators such as TNF-α or IL-6 (tolerance) (p < 0.05). On a functional level, trained neutrophils displayed increased phagocytic activity and LFA-1 expression as well as migrational capacity and CD11a expression, whereas tolerant neutrophils show contrasting effects in vitro. Mechanistically, TLR4/MyD88/PI3Ks regulate the activation of p65, which controls memory-like responses in mouse bone marrow neutrophils (p < 0.05). Our results open a new window for further in vitro studies on memory-like inflammatory responses of short-lived innate immune cells such as neutrophils.

scholarly journals Trained Immunity

2020 ◽  
Author(s):  
Helin Tercan ◽  
Niels P. Riksen ◽  
Leo A.B. Joosten ◽  
Mihai G. Netea ◽  
Siroon Bekkering
Keyword(s):  
Immune Cells ◽  
Inflammatory Diseases ◽  
Oxidized Ldl ◽  
Density Lipoprotein ◽  
Innate Immune ◽  
Immune Memory ◽  
Innate Immune Cells ◽  
Antigen Specificity ◽  
Trained Immunity

Adaptive immune responses are characterized by antigen specificity and induction of lifelong immunologic memory. Recently, it has been reported that innate immune cells can also build immune memory characteristics—a process termed trained immunity. Trained immunity describes the persistent hyperresponsive phenotype that innate immune cells can develop after brief stimulation. Pathogenic stimuli such as microorganisms, and also endogenous molecules including uric acid, oxidized LDL (low-density lipoprotein), and catecholamines, are capable of inducing memory in monocytes and macrophages. While trained immunity provides favorable cross-protection in the context of infectious diseases, the heightened immune response can be maladaptive in diseases driven by chronic systemic inflammation, such as atherosclerosis. Trained immunity is maintained by distinct epigenetic and metabolic mechanisms and persists for at least several months in vivo due to reprogramming of myeloid progenitor cells. Additionally, certain nonimmune cells are also found to exhibit trained immunity characteristics. Thus, trained immunity presents an exciting framework to develop new approaches to vaccination and also novel pharmacological targets in the treatment of inflammatory diseases.

scholarly journals Contribution ofIn Vivoand Organotypic 3D Models to Understanding the Role of Macrophages and Neutrophils in the Pathogenesis of Psoriasis

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Isabelle Lorthois ◽  
Daniel Asselineau ◽  
Nathalie Seyler ◽  
Roxane Pouliot
Keyword(s):  
Immune Cells ◽  
Skin Disease ◽  
Immune Cell ◽  
3D Models ◽  
Current Data ◽  
Innate Immune ◽  
Innate Immune Cells

Psoriasis, a common chronic immune-mediated skin disease, is histologically characterized by a rapid keratinocyte turnover and differentiation defects. Key insights favor the idea that T cells are not the only key actors involved in the inflammatory process. Innate immune cells, more precisely neutrophils and macrophages, provide specific signals involved in the initiation and the maintenance of the pathogenesis. Current data from animal models and, to a lesser extent, three-dimensionalin vitromodels have confirmed the interest in leaning towards other immune cell types as a potential new cellular target for the treatment of the disease. Although these models do not mimic the complex phenotype nor all human features of psoriasis, their development is necessary and essential to better understand reciprocal interactions between skin cells and innate immune cells and to emphasize the crucial importance of the local lesional microenvironment. In this review, through the use ofin vivoand 3D organotypic models, we aim to shed light on the crosstalk between epithelial and immune components and to discuss the role of secreted inflammatory molecules in the development of this chronic skin disease.

scholarly journals Fra-2 Expression in Osteoblasts Regulates Systemic Inflammation and Lung Injury through Osteopontin

2018 ◽  
Vol 38 (22) ◽  
Author(s):  
Yubin Luo ◽  
Bettina Grötsch ◽  
Nicole Hannemann ◽  
Maria Jimenez ◽  
Natacha Ipseiz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lung Injury ◽  
Inflammatory Response ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Bone Marrow Microenvironment ◽  
Innate Immune ◽  
Bone Marrow Niche ◽  
Innate Immune Cells ◽  
Molecular Changes

ABSTRACT Inflammatory responses require mobilization of innate immune cells from the bone marrow. The functionality of this process depends on the state of the bone marrow microenvironment. We therefore hypothesized that molecular changes in osteoblasts, which are essential stromal cells of the bone marrow microenvironment, influence the inflammatory response. Here, we show that osteoblast-specific expression of the AP-1 transcription factor Fra-2 (Fra-2Ob-tet) induced a systemic inflammatory state with infiltration of neutrophils and proinflammatory macrophages into the spleen and liver as well as increased levels of proinflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). By in vivo inhibition of osteopontin (OPN) in Fra-2Ob-tet mice, we demonstrated that this process was dependent on OPN expression, which mediates alterations of the bone marrow niche. OPN expression was transcriptionally enhanced by Fra-2 and stimulated mesenchymal stem cell (MSC) expansion. Furthermore, in a murine lung injury model, Fra-2Ob-tet mice showed increased inflammatory responses and more severe disease features via an enhanced and sustained inflammatory response to lipopolysaccharide (LPS). Our findings demonstrate for the first time that molecular changes in osteoblasts influence the susceptibility to inflammation by altering evasion of innate immune cells from the bone marrow space.

IFNy Regulates the Balance Between Monocyte and Neutrophil Production During Immune Activation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1562-1562
Author(s):  
Alexander M. de Bruin ◽  
Ivo Touw ◽  
Martijn A. Nolte
Keyword(s):  
Bone Marrow ◽  
Immune Cells ◽  
Conflicts Of Interest ◽  
Myeloid Cells ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Proliferation And Differentiation ◽  
Semi Solid ◽  
Deficient Mice

Abstract Abstract 1562 Recruitment of the appropriate cells from the innate immune system to sites of infection is essential for the defense against pathogens. Depending on the type of invading pathogen, infection induces a rapid release from innate immune cells from the bone marrow, followed by an increased production of those myeloid cells that are most suitable to assist the ensuing immune response in the rapid eradication of the pathogen. However, it is thus far poorly understood what the cellular and molecular mechanism is that underlies this change in hematopoiesis. Using a mouse model with increased numbers of IFNγ-producing T cells in the bone marrow, we have previously found that IFNg plays an important role in the production of myeloid cells and can directly inhibit the formation of eosinophils (De Bruin et al., Blood. 2010 Jun 29). Here we demonstrate that IFNg also skews the balance between monocyte and neutrophil production in the direction of the monocytes. Increased monocyte production was also observed in WT mice infected with LCMV, which was IFNg-dependent, as it was not observed in IFNg-deficient mice. Subsequently, we set out to investigate how IFNγ can modulate the balance between monocyte and neutrophil production. We found that IFNγ reduces the proliferation and differentiation of murine hematopoietic progenitors in vitro in response to G-CSF, while M-CSF responses were not inhibited, but even slightly increased. In addition, IFNγ reduces the capacity of GMPs to form granulocyte colonies in semi-solid cultures and increases their ability to form monocyte/macrophage colonies. On a molecular level, we demonstrate that IFNγ induces a strong upregulation of SOCS3 levels and thereby reduces the phosphorylation of STAT3 in response to G-CSF, thus explaining the reduction in granulocyte formation. The expression levels of M-CSF-R and G-CSF-R by GMPs were not affected by IFNγ, but we found that IFNγ does induce the expression of the monocyte-inducing transcription factors PU.1 and IRF8 in these cells. In conclusion, these data demonstrate that IFNγ can direct myelopoiesis in a lineage-specific manner, thereby modulating the production of the appropriate type of innate immune cells required to combat infection. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Oral Exposure to House Dust Mite Activates Intestinal Innate Immunity

Foods ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 561
Author(s):  
Sara Benedé ◽  
Leticia Pérez-Rodríguez ◽  
Mónica Martínez-Blanco ◽  
Elena Molina ◽  
Rosina López-Fandiño
Keyword(s):  
House Dust ◽  
House Dust Mite ◽  
Immune Cells ◽  
Oral Route ◽  
Innate Immune ◽  
Oral Exposure ◽  
Lymphoid Tissues ◽  
Innate Immune Cells ◽  
Dust Mite

Scope: House dust mite (HDM) induces Th2 responses in lungs and skin, but its effects in the intestine are poorly known. We aimed to study the involvement of HDM in the initial events that would promote sensitization through the oral route and eventually lead to allergy development. Methods and results: BALB/c mice were exposed intragastrically to proteolytically active and inactive HDM, as such, or in combination with egg white (EW), and inflammatory and type 2 responses were evaluated. Oral administration of HDM, by virtue of its proteolytic activity, promoted the expression, in the small intestine, of genes encoding tight junction proteins, proinflammatory and Th2-biasing cytokines, and it caused expansion of group 2 innate immune cells, upregulation of Th2 cytokines, and dendritic cell migration and activation. In lymphoid tissues, its proteolytically inactivated counterpart also exerted an influence on the expression of surface DC molecules involved in interactions with T cells and in Th2 cell differentiation, which was confirmed in in vitro experiments. However, in our experimental setting we did not find evidence for the promotion of sensitization to coadministered EW. Conclusion: Orally administered HDM upregulates tissue damage factors and also acts as an activator of innate immune cells behaving similarly to potent oral Th2 adjuvants.

scholarly journals The Potential Neuroprotective Role of Free and Encapsulated Quercetin Mediated by miRNA against Neurological Diseases

Nutrients ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 1318
Author(s):  
Tarek Benameur ◽  
Raffaella Soleti ◽  
Chiara Porro
Keyword(s):  
Inflammatory Responses ◽  
Pathological Condition ◽  
Neurological Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
In Vivo Studies ◽  
Innovative Drug ◽  
Chronic Neuroinflammation

Chronic neuroinflammation is a pathological condition of numerous central nervous system (CNS) diseases such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis and many others. Neuroinflammation is characterized by the microglia activation and concomitant production of pro-inflammatory cytokines leading to an increasing neuronal cell death. The decreased neuroinflammation could be obtained by using natural compounds, including flavonoids known to modulate the inflammatory responses. Among flavonoids, quercetin possess multiple pharmacological applications including anti-inflammatory, antitumoral, antiapoptotic and anti-thrombotic activities, widely demonstrated in both in vitro and in vivo studies. In this review, we describe the recent findings about the neuroprotective action of quercetin by acting with different mechanisms on the microglial cells of CNS. The ability of quercetin to influence microRNA expression represents an interesting skill in the regulation of inflammation, differentiation, proliferation, apoptosis and immune responses. Moreover, in order to enhance quercetin bioavailability and capacity to target the brain, we discuss an innovative drug delivery system. In summary, this review highlighted an important application of quercetin in the modulation of neuroinflammation and prevention of neurological disorders.

Expression of human adenosine deaminase in murine hematopoietic cells

1988 ◽  
Vol 8 (12) ◽  
pp. 5116-5125
Author(s):  
J W Belmont ◽  
G R MacGregor ◽  
K Wager-Smith ◽  
F A Fletcher ◽  
K A Moore ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adenosine Deaminase ◽  
High Titer ◽  
Virus Production ◽  
Marrow Transplant ◽  
Mouse Bone Marrow ◽  
Regulation Of Expression ◽  
Murine Bone Marrow

Multiple replication-defective retrovirus vectors were tested for their ability to transfer and express human adenosine deaminase in vitro and in vivo in a mouse bone marrow transplantation model. High-titer virus production was obtained from vectors by using both a retrovirus long terminal repeat promoter and internal transcriptional units with human c-fos and herpes virus thymidine kinase promoters. After infection of primary murine bone marrow with one of these vectors, human adenosine deaminase was detected in 60 to 85% of spleen colony-forming units and in the blood of 14 of 14 syngeneic marrow transplant recipients. This system offers the opportunity to assess methods for increasing efficiency of gene transfer, for regulation of expression of foreign genes in hematopoietic progenitors, and for long-term measurement of the stability of expression in these cells.

Abstract 1772: Cardiomyocyte Damage-Released S100A1 Protein Evokes A Proinflammatory Phenotype In Cardiac Fibroblasts

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
David Rohde ◽  
Melanie Boerries ◽  
Herzog Nicole ◽  
Gang Qiu ◽  
Philipp Ehlermann ◽  
...  
Keyword(s):  
Western Blotting ◽  
Immune Cells ◽  
Nuclear Translocation ◽  
Cardiac Fibroblasts ◽  
Innate Immune ◽  
Host Cells ◽  
Boyden Chamber ◽  
Innate Immune Cells ◽  
Danger Signal

Background: S100A1, a cardiomyocyte specific inotropic calcium sensor protein, is released from infarcted human myocardium in the extracellular environment and circulation, reaching peak serum levels (1–2 μM) 8–9 hours after clinical onset. As growing evidence indicates that S100 proteins can act as pre-existing danger signals triggering the innate immune system into action upon release from injured host cells, we hypothesized that damage-released S100A1 can act as a cardiac danger signal alerting innate immune cells. Methods and Results: Here we report for the first time that necrotic cardiomyocytes release S100A1 protein in vitro, which is exclusively internalized by cardiac fibroblasts (CFs) in a clathrin- and caveolin-independent manner as shown by IF. Internalized S100A1 specifically activated MAPKs/SAPKs (p38, ERK1/2 and JNK) resulting in nuclear translocation of p65 (NF-kB) as assessed by Western blotting, EMSA and IF. In turn, S100A1 triggered an inflammatory gene program in CFs including enhanced expression of adhesion molecules, integrins, chemokines and cytokines including I-CAM, V-CAM, CD11b/18, IL1-alpha, MCP-1, TNF-alpha, SDF-1 among others as obtained by RT-PCR, Western blotting and ELISA. This resulted in enhanced chemoattraction and adhesion of monocytotic and stem cells to S100A1-activated CF as shown by Boyden-chamber and adhesion assays. In line with their proinflammatory transition, S100A1-activated CFs exhibited decreased collagen-1/-3 expression and de-novo collagen production, enhanced collagenolytic MMP-9 abundance and activity and increased levels of the antiangiogenic matricellular factor thrombospondin-2 reflecting extracellular matrix net degradation. Importantly, the immun-modulatory and antifibrotic actions of S100A1 protein in vitro were restricted to CFs, RAGE independent and occurred at concentrations (0.1–1 μM) that were found in patients after AMI. Conclusion: Our in vitro results indicate that S100A1 has the properties of a pre-exisiting endogenous cardiomyocyte danger signal transforming cardiac fibroblasts into immunmodulatory cells that might recruit innate immune cells to the site of cardiac injury and link cardiomyocyte damage to post-MI inflammation.

scholarly journals Hyperglycemic Memory of Innate Immune Cells Promotes In Vitro Proinflammatory Responses of Human Monocytes and Murine Macrophages

2021 ◽  
pp. ji1901348
Author(s):  
Kathrin Thiem ◽  
Samuel T. Keating ◽  
Mihai G. Netea ◽  
Niels P. Riksen ◽  
Cees J. Tack ◽  
...  
Keyword(s):  
Immune Cells ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Human Monocytes ◽  
Murine Macrophages ◽  
Proinflammatory Responses

scholarly journals Inflammatory Responses during Tumour Initiation: From Zebrafish Transgenic Models of Cancer to Evidence from Mouse and Man

2020 ◽  
Author(s):  
Abigail Elliot ◽  
Henna Myllymäki ◽  
Yi Feng
Keyword(s):  
Immune Cells ◽  
Cancer Biology ◽  
Inflammatory Responses ◽  
Live Imaging ◽  
Innate Immune ◽  
Leukocyte Recruitment ◽  
Innate Immune Cells ◽  
Neoplastic Cells ◽  
Tumour Development ◽  
Tumour Initiation

The zebrafish is now an important model organism for cancer biology studies and provides some unique and complementary opportunities in comparison to the mammalian equivalent. The translucency of zebrafish has allowed in vivo live imaging studies of tumour initiation and progression at the cellular level thus providing novel insights into our understanding of cancer. Here we summarise and discuss available transgenic zebrafish tumour models and what we have gleaned from them with respect to cancer inflammation. In particular, we focus on the host inflammatory response toward transformed cells during the pre-neoplastic stage of tumour development. We discuss features of tumour associated macrophages and neutrophils in mammalian models and present evidence which supports the idea that these inflammatory cells promote early stage tumour development and progression. Direct live imaging of tumour initiation in zebrafish models has shown that the intrinsic inflammation induced by pre-neoplastic cells is tumour promoting. Signals mediating leukocyte recruitment to pre-neoplastic cells in zebrafish correspond to signals mediating leukocyte recruitment in mammalian tumours. The activation state of macrophages and neutrophils recruited to pre-neoplastic cells appears to be heterogenous, as seen in mammalian models, which provides an opportunity to study the plasticity of innate immune cells during tumour initiation. Although several potential mechanisms are described that might mediate the trophic function of innate immune cells during tumour initiation in zebrafish, there are several unknowns that are yet to be resolved. Rapid advancement of genetic tools and imaging technologies for zebrafish will facilitate research into the mechanisms that modulate leukocyte function during tumour initiation and identify targets for cancer prevention.

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