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

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.

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

Circulation ◽

10.1161/circ.118.suppl_18.s_386-c ◽

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.

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Impact of class A, B and C CpG-oligodeoxynucleotides on in vitro activation of innate immune cells in human immunodeficiency virus-1 infected individuals

Immunology ◽

10.1111/j.1365-2567.2007.02530.x ◽

2007 ◽

Vol 120 (4) ◽

pp. 526-535 ◽

Cited By ~ 39

Author(s):

Jeffrey A. Martinson ◽

Allan R. Tenorio ◽

Carlos J. Montoya ◽

Lena Al-Harthi ◽

Carolyne N. Gichinga ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Immune Cells ◽

Innate Immune ◽

Innate Immune Cells ◽

Cpg Oligodeoxynucleotides ◽

Class A ◽

Immunodeficiency Virus ◽

In Vitro Activation ◽

Human Immunodeficiency Virus 1

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The Life Cycle Stages of Pneumocystis murina Have Opposing Effects on the Immune Response to This Opportunistic Fungal Pathogen

Infection and Immunity ◽

10.1128/iai.00519-16 ◽

2016 ◽

Vol 84 (11) ◽

pp. 3195-3205 ◽

Cited By ~ 9

Author(s):

Heather M. Evans ◽

Grady L. Bryant ◽

Beth A. Garvy

Keyword(s):

Cell Wall ◽

Life Cycle ◽

Immune Responses ◽

Immune Cells ◽

Innate Immune ◽

Innate Immune Cells ◽

Content Type ◽

Life Cycle Stages ◽

Ifn Γ

The cell wall β-glucans of Pneumocystis cysts have been shown to stimulate immune responses in lung epithelial cells, dendritic cells, and alveolar macrophages. Little is known about how the trophic life forms, which do not have a fungal cell wall, interact with these innate immune cells. Here we report differences in the responses of both neonatal and adult mice to the trophic and cystic life cycle stages of Pneumocystis murina . The adult and neonatal immune responses to infection with Pneumocystis murina trophic forms were less robust than the responses to infection with a physiologically normal mixture of cysts and trophic forms. Cysts promoted the recruitment of nonresident innate immune cells and T and B cells into the lungs. Cysts, but not trophic forms, stimulated increased concentrations of the cytokine gamma interferon (IFN-γ) in the alveolar spaces and an increase in the percentage of CD4 + T cells that produce IFN-γ. In vitro , bone marrow-derived dendritic cells (BMDCs) stimulated with cysts produced the proinflammatory cytokines interleukin 1β (IL-1β) and IL-6. In contrast, trophic forms suppressed antigen presentation to CD4 + T cells, as well as the β-glucan-, lipoteichoic acid (LTA)-, and lipopolysaccharide (LPS)-induced production of interleukin 1β (IL-1β), IL-6, and tumor necrosis factor alpha (TNF-α) by BMDCs. The negative effects of trophic forms were not due to ligation of mannose receptor. Our results indicate that optimal innate and adaptive immune responses to Pneumocystis species are dependent on stimulation with the cyst life cycle stage. Conversely, trophic forms suppress β-glucan-induced proinflammatory responses in vitro , suggesting that the trophic forms dampen cyst-induced inflammation in vivo .

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Keratinocytes contribute intrinsically to psoriasis upon loss of Tnip1 function

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1606996113 ◽

2016 ◽

Vol 113 (41) ◽

pp. E6162-E6171 ◽

Cited By ~ 33

Author(s):

Sirish K. Ippagunta ◽

Ruchika Gangwar ◽

David Finkelstein ◽

Peter Vogel ◽

Stephane Pelletier ◽

...

Keyword(s):

Immune Cells ◽

Inflammatory Process ◽

Immune Cell ◽

Genetic Alterations ◽

Innate Immune ◽

Negative Regulator ◽

Specific Gene ◽

Innate Immune Cells ◽

Chemokine Production

Psoriasis is a chronic inflammatory skin disease with a clear genetic contribution, characterized by keratinocyte proliferation and immune cell infiltration. Various closely interacting cell types, including innate immune cells, T cells, and keratinocytes, are known to contribute to inflammation. Innate immune cells most likely initiate the inflammatory process by secretion of IL-23. IL-23 mediates expansion of T helper 17 (Th17) cells, whose effector functions, including IL-17A, activate keratinocytes. Keratinocyte activation in turn results in cell proliferation and chemokine expression, the latter of which fuels the inflammatory process through further immune cell recruitment. One question that remains largely unanswered is how genetic susceptibility contributes to this process and, specifically, which cell type causes disease due to psoriasis-specific genetic alterations. Here we describe a mouse model based on the human psoriasis susceptibility locus TNIP1, also referred to as ABIN1, whose gene product is a negative regulator of various inflammatory signaling pathways, including the Toll-like receptor pathway in innate immune cells. We find that Tnip1-deficient mice recapitulate major features of psoriasis on pathological, genomic, and therapeutic levels. Different genetic approaches, including tissue-specific gene deletion and the use of various inflammatory triggers, reveal that Tnip1 controls not only immune cells, but also keratinocyte biology. Loss of Tnip1 in keratinocytes leads to deregulation of IL-17–induced gene expression and exaggerated chemokine production in vitro and overt psoriasis-like inflammation in vivo. Together, the data establish Tnip1 as a critical regulator of IL-17 biology and reveal a causal role of keratinocytes in the pathogenesis of psoriasis.

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Unmetabolized quetiapine exerts an in vitro effect on innate immune cells by modulating inflammatory response and neutrophil extracellular trap formation

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2020.110497 ◽

2020 ◽

Vol 131 ◽

pp. 110497

Author(s):

Bárbara Osmarin Turra ◽

Fernanda Barbisan ◽

Verônica Farina Azzolin ◽

Cibele Ferreira Teixeira ◽

Thamara Flores ◽

...

Keyword(s):

Inflammatory Response ◽

Immune Cells ◽

Innate Immune ◽

Neutrophil Extracellular Trap ◽

Innate Immune Cells ◽

Trap Formation ◽

Extracellular Trap ◽

Vitro Effect

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Dissecting the phenotypic and functional heterogeneity of mouse inflammatory osteoclasts by the expression of Cx3cr1

eLife ◽

10.7554/elife.54493 ◽

2020 ◽

Vol 9 ◽

Author(s):

Maria-Bernadette Madel ◽

Lidia Ibáñez ◽

Thomas Ciucci ◽

Julia Halper ◽

Matthieu Rouleau ◽

...

Keyword(s):

T Cells ◽

Immune Cells ◽

Osteoclast Differentiation ◽

Bone Destruction ◽

Suppressive Effect ◽

Innate Immune ◽

Innate Immune Cells ◽

Functional Heterogeneity ◽

Functional Aspects

Bone destruction relies on interactions between bone and immune cells. Bone-resorbing osteoclasts (OCLs) were recently identified as innate immune cells activating T cells toward tolerance or inflammation. Thus, pathological bone destruction not only relies on increased osteoclast differentiation, but also on the presence of inflammatory OCLs (i-OCLs), part of which express Cx3cr1. Here, we investigated the contribution of mouse Cx3cr1+ and Cx3cr1neg i-OCLs to bone loss. We showed that Cx3cr1+ and Cx3cr1neg i-OCLs differ considerably in transcriptional and functional aspects. Cx3cr1neg i-OCLs have a high ability to resorb bone and activate inflammatory CD4+ T cells. Although Cx3cr1+ i-OCLs are associated with inflammation, they resorb less and have in vitro an immune-suppressive effect on Cx3cr1neg i-OCLs, mediated by PD-L1. Our results provide new insights into i-OCL heterogeneity. They also reveal that different i-OCL subsets may interact to regulate inflammation. This contributes to a better understanding and prevention of inflammatory bone destruction.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22189803 ◽

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.

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Bacterial lipolysis of immune-activating ligands promotes evasion of innate defenses

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1817248116 ◽

2019 ◽

Vol 116 (9) ◽

pp. 3764-3773 ◽

Cited By ~ 15

Author(s):

Xi Chen ◽

Francis Alonzo

Keyword(s):

Fatty Acids ◽

Immune Cells ◽

Mammalian Cells ◽

Pathogenic Bacteria ◽

Innate Immune ◽

Host Immune System ◽

Immune Recognition ◽

Innate Immune Cells ◽

Gram Positive

Commensal and pathogenic bacteria hydrolyze host lipid substrates with secreted lipases and phospholipases for nutrient acquisition, colonization, and infection. Bacterial lipase activity on mammalian lipids and phospholipids can promote release of free fatty acids from lipid stores, detoxify antimicrobial lipids, and facilitate membrane dissolution. The gram-positive bacteriumStaphylococcus aureussecretes at least two lipases, Sal1 and glycerol ester hydrolase (Geh), with specificities for short- and long-chain fatty acids, respectively, each with roles in the hydrolysis of environmental lipids. In a recent study from our group, we made the unexpected observation that Geh released byS. aureusinhibits activation of innate immune cells. Herein, we investigated the possibility thatS. aureuslipases interface with the host immune system to blunt innate immune recognition of the microbe. We found that the Geh lipase, but not otherS. aureuslipases, prevents activation of innate cells in culture. Mutation ofgehleads to enhancement of proinflammatory cytokine production during infection, increased innate immune activity, and improved clearance of the bacterium in infected tissue. These in vitro and in vivo effects on innate immunity were not due to direct functions of the lipase on mammalian cells, but rather a result of inactivation ofS. aureuslipoproteins, a major pathogen-associated molecular pattern (PAMP) of extracellular gram-positive bacteria, via ester hydrolysis. Altogether, these studies provide insight into an adaptive trait that masks microbial recognition by innate immune cells through targeted inactivation of a broadly conserved PAMP.

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