scholarly journals Deletion of cftr leads to an excessive neutrophilic response and defective tissue repair in a zebrafish model of sterile inflammation

2019 ◽  
Author(s):  
Audrey Bernut ◽  
Catherine A. Loynes ◽  
R. Andres Floto ◽  
Stephen A. Renshaw
Keyword(s):  
Cystic Fibrosis ◽  
Tissue Repair ◽  
Cell Function ◽  
Immune Cell ◽  
Genetic Disorder ◽  
Innate Immune ◽  
Lung Damage ◽  
Tanshinone Iia ◽  
Sterile Inflammation ◽  
Inflammatory Status

AbstractInflammation-related progressive lung destruction is the leading causes of premature death in cystic fibrosis (CF), a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. However, therapeutic targeting of inflammation has been hampered by a lack of understanding of the links between a dysfunctional CFTR and the deleterious innate immune response in CF. Herein, we used CFTR-depleted zebrafish larvae as an innovative in vivo vertebrate model, mimicking aspects of the inflammatory pathology of CF-related lung, to understand how CFTR dysfunction leads to abnormal inflammatory status in CF.We show that impaired CFTR-mediated inflammation correlates with an exuberant neutrophilic response after injury: CF zebrafish exhibit enhanced and sustained accumulation of neutrophils at wounds. Excessive epithelial oxidative responses drive enhanced neutrophil recruitment towards wounds. Persistence of neutrophils at inflamed sites is associated with impaired reverse migration of neutrophils and reduction in neutrophil apoptosis. As a consequence, the increased number of neutrophils at wound sites causes tissue damage and abnormal tissue repair. Importantly, the pro-resolution molecule Tanshinone IIA successfully re-balances inflammation both by accelerating inflammation resolution and by improving tissue repair in CFTR-deficient animal.Larval zebrafish giving a unique insight into innate immune cell function in CFTR deficiency, our findings bring important new understanding of the mechanisms underlying the inflammatory pathology in CF, which could be addressed therapeutically to prevent inflammatory lung damage in CF patients with potential improvements in disease outcomes.

scholarly journals MMP-19 deficiency causes aggravation of colitis due to defects in innate immune cell function

2015 ◽  
Vol 9 (4) ◽  
pp. 974-985 ◽  
Author(s):  
R Brauer ◽  
J Tureckova ◽  
I Kanchev ◽  
M Khoylou ◽  
J Skarda ◽  
...  
Keyword(s):  
Cell Function ◽  
Immune Cell ◽  
Innate Immune ◽  
Innate Immune Cell ◽  
Immune Cell Function

scholarly journals Developmental maturation of innate immune cell function correlates with susceptibility to central nervous system autoimmunity

2013 ◽  
Vol 43 (8) ◽  
pp. 2078-2088 ◽  
Author(s):  
Deetje Hertzenberg ◽  
Klaus Lehmann-Horn ◽  
Silke Kinzel ◽  
Veronika Husterer ◽  
Petra D. Cravens ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cell Function ◽  
Immune Cell ◽  
Innate Immune ◽  
Innate Immune Cell ◽  
Immune Cell Function ◽  
Developmental Maturation

scholarly journals Flavored e-cigarette liquids and cinnamaldehyde impair respiratory innate immune cell function

2017 ◽  
Vol 313 (2) ◽  
pp. L278-L292 ◽  
Author(s):  
Phillip W. Clapp ◽  
Erica A. Pawlak ◽  
Justin T. Lackey ◽  
James E. Keating ◽  
Steven L. Reeber ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Nk Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Innate Immune ◽  
Neutrophil Extracellular Trap ◽  
Immune Functions ◽  
Immune Cell Function ◽  
Functional Responses ◽  
Macrophage Phagocytosis

Innate immune cells of the respiratory tract are the first line of defense against pathogenic and environmental insults. Failure of these cells to perform their immune functions leaves the host susceptible to infection and may contribute to impaired resolution of inflammation. While combustible tobacco cigarettes have been shown to suppress respiratory immune cell function, the effects of flavored electronic cigarette liquids (e-liquids) and individual flavoring agents on respiratory immune cell responses are unknown. We investigated the effects of seven flavored nicotine-free e-liquids on primary human alveolar macrophages, neutrophils, and natural killer (NK) cells. Cells were challenged with a range of e-liquid dilutions and assayed for their functional responses to pathogenic stimuli. End points included phagocytic capacity (neutrophils and macrophages), neutrophil extracellular trap formation, proinflammatory cytokine production, and cell-mediated cytotoxic response (NK cells). E-liquids were then analyzed via mass spectrometry to identify individual flavoring components. Three cinnamaldehyde-containing e-liquids exhibited dose-dependent broadly immunosuppressive effects. Quantitative mass spectrometry was used to determine concentrations of cinnamaldehyde in each of the three e-liquids, and cells were subsequently challenged with a range of cinnamaldehyde concentrations. Cinnamaldehyde alone recapitulated the impaired function observed with e-liquid exposures, and cinnamaldehyde-induced suppression of macrophage phagocytosis was reversed by addition of the small-molecule reducing agent 1,4-dithiothreitol. We conclude that cinnamaldehyde has the potential to impair respiratory immune cell function, illustrating an immediate need for further toxicological evaluation of chemical flavoring agents to inform regulation governing their use in e-liquid formulations.

scholarly journals Mutant p53 suppresses innate immune signaling to promote tumorigenesis

2020 ◽  
Author(s):  
Monisankar Ghosh ◽  
Suchandrima Saha ◽  
Julie Bettke ◽  
Rachana Nagar ◽  
Alejandro Parrales ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Cell Function ◽  
Immune Cell ◽  
Nuclear Translocation ◽  
Innate Immune ◽  
Tumor Control ◽  
Mutant P53 ◽  
Dna Sensing ◽  
Immune Signaling ◽  
Innate Immune Signaling

ABSTRACTMutations in the p53 tumor suppressor occur very frequently in human cancer. Often, such mutations lead to the constitutive overproduction of mutant p53 (mtp53) proteins, which can exert a cancer-promoting gain-of-function (GOF). We have identified a novel mechanism by which mtp53 controls both cell-autonomous and non-cell autonomous signaling to promote cancer cell survival and suppress tumor immune surveillance. Mtp53 interferes with the function of the cytoplasmic DNA sensing machinery, cGAS-STING-TBK1-IRF3, that controls the activation of the innate immune response. We find that mtp53, but not wildtype p53, binds to TANK binding protein kinase (TBK1) and inhibits both its basal and agonist-induced activity. The association of mtp53 with TBK1 prevents the formation of a trimeric complex between TBK1-STING-IRF3, which is required for activation, nuclear translocation and transcriptional activity of IRF3. Mtp53 knockdown restores TBK1 activity, resulting in the transcriptional induction of IRF3 target genes and IRF3-dependent apoptosis. Furthermore, inactivation of innate immune signaling by mtp53 alters cytokine production resulting in immune evasion. Restored TBK1 signaling was sufficient to bypass mtp53 and reactivate cell-autonomous and non-cell autonomous tumor control. Thus, overriding mtp53’s inhibition of this cytosolic DNA sensing pathway may ultimately lead to restored immune cell function and cancer cell eradication.

scholarly journals Efferocytosis potentiates the expression of arachidonate 15-lipoxygenase (ALOX15) in alternatively activated human macrophages through LXR activation

2020 ◽  
Author(s):  
Ryan G. Snodgrass ◽  
Yvonne Benatzy ◽  
Tobias Schmid ◽  
Dmitry Namgaladze ◽  
Malwina Mainka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tissue Repair ◽  
Cell Function ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Th2 Cytokines ◽  
Alternatively Activated Macrophages ◽  
Anti Inflammatory ◽  
Alternatively Activated

Abstract Macrophages acquire anti-inflammatory and proresolving functions to facilitate resolution of inflammation and promote tissue repair. While alternatively activated macrophages (AAMs), also referred to as M2 macrophages, polarized by type 2 (Th2) cytokines IL-4 or IL-13 contribute to the suppression of inflammatory responses and play a pivotal role in wound healing, contemporaneous exposure to apoptotic cells (ACs) potentiates the expression of anti-inflammatory and tissue repair genes. Given that liver X receptors (LXRs), which coordinate sterol metabolism and immune cell function, play an essential role in the clearance of ACs, we investigated whether LXR activation following engulfment of ACs selectively potentiates the expression of Th2 cytokine-dependent genes in primary human AAMs. We show that AC uptake simultaneously upregulates LXR-dependent, but suppresses SREBP-2-dependent gene expression in macrophages, which are both prevented by inhibiting Niemann–Pick C1 (NPC1)-mediated sterol transport from lysosomes. Concurrently, macrophages accumulate sterol biosynthetic intermediates desmosterol, lathosterol, lanosterol, and dihydrolanosterol but not cholesterol-derived oxysterols. Using global transcriptome analysis, we identify anti-inflammatory and proresolving genes including interleukin-1 receptor antagonist (IL1RN) and arachidonate 15-lipoxygenase (ALOX15) whose expression are selectively potentiated in macrophages upon concomitant exposure to ACs or LXR agonist T0901317 (T09) and Th2 cytokines. We show priming macrophages via LXR activation enhances the cellular capacity to synthesize inflammation-suppressing specialized proresolving mediator (SPM) precursors 15-HETE and 17-HDHA as well as resolvin D5. Silencing LXRα and LXRβ in macrophages attenuates the potentiation of ALOX15 expression by concomitant stimulation of ACs or T09 and IL-13. Collectively, we identify a previously unrecognized mechanism of regulation whereby LXR integrates AC uptake to selectively shape Th2-dependent gene expression in AAMs.

Effect of PTEN inactivating germline mutations on innate immune cell function and thyroid cancer-induced macrophages in patients with PTEN hamartoma tumor syndrome

Oncogene ◽  
2019 ◽  
Vol 38 (19) ◽  
pp. 3743-3755 ◽  
Author(s):  
Yvette J. E. Sloot ◽  
Katrin Rabold ◽  
Mihai G. Netea ◽  
Johannes W. A. Smit ◽  
Nicoline Hoogerbrugge ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cell Function ◽  
Immune Cell ◽  
Germline Mutations ◽  
Innate Immune ◽  
Innate Immune Cell ◽  
Immune Cell Function ◽  
Pten Hamartoma Tumor Syndrome

scholarly journals Observations of, and Insights into, Cystic Fibrosis Mucus Heterogeneity in the Pre-Modulator Era: Sputum Characteristics, DNA and Glycoprotein Content, and Solubilization Time

2020 ◽  
Vol 1 (1) ◽  
pp. 8-29
Author(s):  
Deborah L. Chance ◽  
Thomas P. Mawhinney
Keyword(s):  
Electron Microscopy ◽  
Cystic Fibrosis ◽  
Respiratory Tract ◽  
Immune Cell ◽  
Dry Weight ◽  
Therapeutic Strategies ◽  
Lung Damage ◽  
Therapeutic Interventions ◽  
3D Analysis ◽  
Predictive Relationship

Airway obstruction with chronic inflammation and infection are major contributors to the lung damage and mortality of cystic fibrosis (CF). A better understanding of the congested milieu of CF airways will aid in improving therapeutic strategies. This article retrospectively reports our observations, and discusses insights gained in the handling and analysis of CF sputa. CF and non-CF mucus samples were surveyed for morphological features by electron microscopy and analyzed for the macromolecular dry weight (MDW), total protein, lipid, carbohydrate, and DNA. Mucus character was investigated with chemical solubilization time as a comparative tool. CF mucus appeared distinctly thick, viscous, and heterogeneous, with neutrophils as the dominant immune cell. CF sputum DNA content varied markedly for and between individuals (~1–10% MDW), as did solubilization times (~1–20 h). CF Sputum DNA up to 7.1% MDW correlated positively with solubilization time, whereas DNA >7.1% MDW correlated negatively. 3D analysis of CF sputa DNA, GP, and solubilization times revealed a dynamic and predictive relationship. Reflecting on the heterogeneous content and character of CF mucus, and the possible interplay in space and time in the respiratory tract of polymeric DNA and mucous glycoproteins, we highlight it’s potential to affect infection-related airway pathologies and the success of therapeutic interventions.

Pathogenesis of ANCA-associated vasculitis: an emerging role for immunometabolism

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_3) ◽  
pp. iii33-iii41
Author(s):  
Emma Leacy ◽  
Gareth Brady ◽  
Mark A Little
Keyword(s):  
Immune Cells ◽  
Metabolic Pathways ◽  
Cell Function ◽  
Immune Cell ◽  
Cell Metabolism ◽  
Innate Immune ◽  
Systemic Autoimmune Disease ◽  
Cellular Activation ◽  
Ample Evidence ◽  
Anca Associated Vasculitis

Abstract ANCA-associated vasculitis (AAV) is a severe systemic autoimmune disease. A key feature of AAV is the presence of Anti-Neutrophil Cytoplasmic Antibodies (ANCA) directed against myeloperoxidase (MPO) or proteinase-3 (PR3). ANCA are key to the pathogenesis of AAV, where they activate innate immune cells to drive inflammation. Pre-activation or ‘priming’ of immune cells appears to be important for complete cellular activation in AAV. The burgeoning field of immunometabolism has illuminated the governance of immune cell function by distinct metabolic pathways. There is ample evidence that the priming events synonymous with AAV alter immune cell metabolism. In this review we discuss the pathogenesis of AAV and its intersection with recent insights into immune cell metabolism.

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